diff --git a/tracer/src/Datadog.Trace/ClrProfiler/AutoInstrumentation/AspNet/HttpModule_Integration.cs b/tracer/src/Datadog.Trace/ClrProfiler/AutoInstrumentation/AspNet/HttpModule_Integration.cs
index 8a23ebc276c6..c9b7e92d111d 100644
--- a/tracer/src/Datadog.Trace/ClrProfiler/AutoInstrumentation/AspNet/HttpModule_Integration.cs
+++ b/tracer/src/Datadog.Trace/ClrProfiler/AutoInstrumentation/AspNet/HttpModule_Integration.cs
@@ -21,31 +21,25 @@ namespace Datadog.Trace.ClrProfiler.AutoInstrumentation.AspNet
         TypeName = "System.Web.Compilation.BuildManager",
         MethodName = "InvokePreStartInitMethodsCore",
         ReturnTypeName = ClrNames.Void,
-        ParameterTypeNames = new[] { "System.Collections.Generic.ICollection`1[System.Reflection.MethodInfo]", "System.Func`1[System.IDisposable]" },
+        ParameterTypeNames = ["System.Collections.Generic.ICollection`1[System.Reflection.MethodInfo]", "System.Func`1[System.IDisposable]"],
         MinimumVersion = "4.0.0",
         MaximumVersion = "4.*.*",
-        IntegrationName = IntegrationName)]
+        IntegrationName = nameof(IntegrationId.AspNet))]
     [Browsable(false)]
     [EditorBrowsable(EditorBrowsableState.Never)]
     public class HttpModule_Integration
     {
-        private const string IntegrationName = nameof(IntegrationId.AspNet);
+        // WARNING: Do not add a static reference to `IDatadogLogger` or reference
+        // anything related to Tracer.Instance etc. This method is called at application
+        // start _before_ the Tracer is initialized; adding additional references could
+        // cause recursion issues and deadlocks in some scenarios, e.g. where there are
+        // multiple apps per app pool.
 
         /// <summary>
         /// Indicates whether we're initializing the HttpModule for the first time
         /// </summary>
         private static int _firstInitialization = 1;
 
-        /// <summary>
-        /// OnMethodBegin callback
-        /// </summary>
-        /// <typeparam name="TTarget">Type of the target</typeparam>
-        /// <typeparam name="TCollection">Type of the collection</typeparam>
-        /// <typeparam name="TFunc">Type of the </typeparam>
-        /// <param name="instance">Instance value, aka `this` of the instrumented method. This method is static so this parameter will always be null</param>
-        /// <param name="methods">The methods to be invoked</param>
-        /// <param name="setHostingEnvironmentCultures">The function to set the environment culture</param>
-        /// <returns>Calltarget state value</returns>
         internal static CallTargetState OnMethodBegin<TTarget, TCollection, TFunc>(TTarget instance, TCollection methods, TFunc setHostingEnvironmentCultures)
         {
             if (Interlocked.Exchange(ref _firstInitialization, 0) != 1)
@@ -61,7 +55,8 @@ internal static CallTargetState OnMethodBegin<TTarget, TCollection, TFunc>(TTarg
             catch
             {
                 // Unable to dynamically register module
-                // Not sure if we can technically log yet or not, so do nothing
+                // We can't log here as it could cause recursion issues and deadlocks in some scenarios
+                // where there are multiple apps per app pool
             }
 
             return CallTargetState.GetDefault();
diff --git a/tracer/src/Datadog.Trace/ClrProfiler/CallTarget/CallTargetInvoker.cs b/tracer/src/Datadog.Trace/ClrProfiler/CallTarget/CallTargetInvoker.cs
index c57c40d206c5..8ee5955982cc 100644
--- a/tracer/src/Datadog.Trace/ClrProfiler/CallTarget/CallTargetInvoker.cs
+++ b/tracer/src/Datadog.Trace/ClrProfiler/CallTarget/CallTargetInvoker.cs
@@ -6,7 +6,9 @@
 
 using System;
 using System.ComponentModel;
+using System.Diagnostics;
 using System.Runtime.CompilerServices;
+using Datadog.Trace.ClrProfiler.AutoInstrumentation.AspNet;
 using Datadog.Trace.ClrProfiler.CallTarget.Handlers;
 
 namespace Datadog.Trace.ClrProfiler.CallTarget;
@@ -18,14 +20,67 @@ namespace Datadog.Trace.ClrProfiler.CallTarget;
 [EditorBrowsable(EditorBrowsableState.Never)]
 public static class CallTargetInvoker
 {
+    // NOTE: Do not add a reference to IDatadogLogger or Tracer.Instance etc here.
+    // On .NET FX, this class may be called _before_ Instrumentation.Initialize, if
+    // there are multiple apps running in the same app pool. Referencing IDatadogLogger
+    // can cause some things (e.g. AppSettings) to initialized too early, which can
+    // cause recursion issues and deadlocks.
+
+#if NETFRAMEWORK
+    private const string NamedSlotName = "Datadog_IISPreInitStart";
+    private static bool _isIisPreStartInitComplete;
+
     static CallTargetInvoker()
     {
-        // The first time the CallTargetInvoker is called
-        // we ensure that the non native parts of the initialization ran
-        // This is required for AOT scenarios where there is no clrprofiler
-        // to inject and run the loader.
-        Instrumentation.InitializeNoNativeParts();
+        // Check if IIS automatic instrumentation has set the AppDomain property to indicate the PreStartInit state
+        // This is added to the startup hook by the CorProfiler in CorProfiler::AddIISPreStartInitFlags()
+        // which sets the value to `false` when the InvokePreStartInitMethods() method starts, and sets it to
+        // `true` after it's finished. Only once it returns to `true` can we start running CallTarget integrations.
+        var state = AppDomain.CurrentDomain.GetData(NamedSlotName);
+        if (state is bool boolState)
+        {
+            // we know we must be in IIS, so we need to check the app domain state
+            _isIisPreStartInitComplete = !boolState;
+        }
+        else
+        {
+            // We could _either_ not be in IIS, or we could be in an IIS app domain that hasn't set the property yet
+            // This can happen when we have multiple apps running in the same app domain.
+            try
+            {
+                // We need to check if we're running in IIS, so that we know whether to _expect_
+                // the IIS PreStartInit AppDomain property to be set. Outside of IIS, it will never be set.
+                // We can't use ProcessHelpers here, because that could cause premature initialization of the
+                // tracer, which could cause recursion issues with IIS PreStartInit code execution
+                var processName = Process.GetCurrentProcess().ProcessName;
+
+                if (processName.Equals("w3wp", StringComparison.OrdinalIgnoreCase) ||
+                    processName.Equals("iisexpress", StringComparison.OrdinalIgnoreCase))
+                {
+                    // We're in IIS, so we know we need to check the AppDomain property
+                    // In previous workarounds for similar issues (e.g. https://github.com/DataDog/dd-trace-dotnet/pull/1157)
+                    // we resorted to checking the callstack to see if it contained
+                    // System.Web.Hosting.HostingEnvironment.Initialize(). That's generally unnecessary here, as
+                    // if we know we're in IIS, we know we should be initialised _eventually_. Plus, checking the
+                    // stack doesn't always work anyway, because if a threadpool thread is injected with a calltarget
+                    // instrumentation, all we see is `Dispatch()`, which is not helpful.
+                    _isIisPreStartInitComplete = false;
+                }
+                else
+                {
+                    // If we're not in IIS, we don't need to run any pre-init checks, so mark as already complete
+                    _isIisPreStartInitComplete = true;
+                }
+            }
+            catch (Exception)
+            {
+                // Error getting process name, have to assume we _aren't_ in IIS,
+                // and that we don't need to wait for the app domain data
+                _isIisPreStartInitComplete = true;
+            }
+        }
     }
+#endif
 
     /// <summary>
     /// Begin Method Invoker
@@ -37,7 +92,7 @@ static CallTargetInvoker()
     [MethodImpl(MethodImplOptions.AggressiveInlining)]
     public static CallTargetState BeginMethod<TIntegration, TTarget>(TTarget? instance)
     {
-        if (IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
+        if (CanExecuteCallTargetIntegration<TIntegration>() && IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
         {
             IntegrationOptions<TIntegration, TTarget>.RecordTelemetry();
             return BeginMethodHandler<TIntegration, TTarget>.Invoke(instance);
@@ -58,7 +113,7 @@ public static CallTargetState BeginMethod<TIntegration, TTarget>(TTarget? instan
     [MethodImpl(MethodImplOptions.AggressiveInlining)]
     public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1>(TTarget? instance, TArg1? arg1)
     {
-        if (IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
+        if (CanExecuteCallTargetIntegration<TIntegration>() && IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
         {
             IntegrationOptions<TIntegration, TTarget>.RecordTelemetry();
             return BeginMethodHandler<TIntegration, TTarget, TArg1>.Invoke(instance, ref arg1);
@@ -81,7 +136,7 @@ public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1>(TTarget?
     [MethodImpl(MethodImplOptions.AggressiveInlining)]
     public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2>(TTarget? instance, TArg1? arg1, TArg2? arg2)
     {
-        if (IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
+        if (CanExecuteCallTargetIntegration<TIntegration>() && IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
         {
             IntegrationOptions<TIntegration, TTarget>.RecordTelemetry();
             return BeginMethodHandler<TIntegration, TTarget, TArg1, TArg2>.Invoke(instance, ref arg1, ref arg2);
@@ -106,7 +161,7 @@ public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2>(T
     [MethodImpl(MethodImplOptions.AggressiveInlining)]
     public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2, TArg3>(TTarget? instance, TArg1? arg1, TArg2? arg2, TArg3? arg3)
     {
-        if (IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
+        if (CanExecuteCallTargetIntegration<TIntegration>() && IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
         {
             IntegrationOptions<TIntegration, TTarget>.RecordTelemetry();
             return BeginMethodHandler<TIntegration, TTarget, TArg1, TArg2, TArg3>.Invoke(instance, ref arg1, ref arg2, ref arg3);
@@ -133,7 +188,7 @@ public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2, T
     [MethodImpl(MethodImplOptions.AggressiveInlining)]
     public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2, TArg3, TArg4>(TTarget? instance, TArg1? arg1, TArg2? arg2, TArg3? arg3, TArg4? arg4)
     {
-        if (IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
+        if (CanExecuteCallTargetIntegration<TIntegration>() && IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
         {
             IntegrationOptions<TIntegration, TTarget>.RecordTelemetry();
             return BeginMethodHandler<TIntegration, TTarget, TArg1, TArg2, TArg3, TArg4>.Invoke(instance, ref arg1, ref arg2, ref arg3, ref arg4);
@@ -162,7 +217,7 @@ public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2, T
     [MethodImpl(MethodImplOptions.AggressiveInlining)]
     public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2, TArg3, TArg4, TArg5>(TTarget? instance, TArg1? arg1, TArg2? arg2, TArg3? arg3, TArg4? arg4, TArg5? arg5)
     {
-        if (IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
+        if (CanExecuteCallTargetIntegration<TIntegration>() && IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
         {
             IntegrationOptions<TIntegration, TTarget>.RecordTelemetry();
             return BeginMethodHandler<TIntegration, TTarget, TArg1, TArg2, TArg3, TArg4, TArg5>.Invoke(instance, ref arg1, ref arg2, ref arg3, ref arg4, ref arg5);
@@ -193,7 +248,7 @@ public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2, T
     [MethodImpl(MethodImplOptions.AggressiveInlining)]
     public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2, TArg3, TArg4, TArg5, TArg6>(TTarget? instance, TArg1? arg1, TArg2? arg2, TArg3? arg3, TArg4? arg4, TArg5? arg5, TArg6? arg6)
     {
-        if (IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
+        if (CanExecuteCallTargetIntegration<TIntegration>() && IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
         {
             IntegrationOptions<TIntegration, TTarget>.RecordTelemetry();
             return BeginMethodHandler<TIntegration, TTarget, TArg1, TArg2, TArg3, TArg4, TArg5, TArg6>.Invoke(instance, ref arg1, ref arg2, ref arg3, ref arg4, ref arg5, ref arg6);
@@ -226,7 +281,7 @@ public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2, T
     [MethodImpl(MethodImplOptions.AggressiveInlining)]
     public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2, TArg3, TArg4, TArg5, TArg6, TArg7>(TTarget? instance, TArg1? arg1, TArg2? arg2, TArg3? arg3, TArg4? arg4, TArg5? arg5, TArg6? arg6, TArg7? arg7)
     {
-        if (IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
+        if (CanExecuteCallTargetIntegration<TIntegration>() && IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
         {
             IntegrationOptions<TIntegration, TTarget>.RecordTelemetry();
             return BeginMethodHandler<TIntegration, TTarget, TArg1, TArg2, TArg3, TArg4, TArg5, TArg6, TArg7>.Invoke(instance, ref arg1, ref arg2, ref arg3, ref arg4, ref arg5, ref arg6, ref arg7);
@@ -261,7 +316,7 @@ public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2, T
     [MethodImpl(MethodImplOptions.AggressiveInlining)]
     public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2, TArg3, TArg4, TArg5, TArg6, TArg7, TArg8>(TTarget? instance, TArg1? arg1, TArg2? arg2, TArg3? arg3, TArg4? arg4, TArg5? arg5, TArg6? arg6, TArg7? arg7, TArg8? arg8)
     {
-        if (IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
+        if (CanExecuteCallTargetIntegration<TIntegration>() && IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
         {
             IntegrationOptions<TIntegration, TTarget>.RecordTelemetry();
             return BeginMethodHandler<TIntegration, TTarget, TArg1, TArg2, TArg3, TArg4, TArg5, TArg6, TArg7, TArg8>.Invoke(instance, ref arg1, ref arg2, ref arg3, ref arg4, ref arg5, ref arg6, ref arg7, ref arg8);
@@ -282,7 +337,7 @@ public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2, T
     [MethodImpl(MethodImplOptions.AggressiveInlining)]
     public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1>(TTarget? instance, ref TArg1? arg1)
     {
-        if (IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
+        if (CanExecuteCallTargetIntegration<TIntegration>() && IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
         {
             IntegrationOptions<TIntegration, TTarget>.RecordTelemetry();
             return BeginMethodHandler<TIntegration, TTarget, TArg1>.Invoke(instance, ref arg1);
@@ -305,7 +360,7 @@ public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1>(TTarget?
     [MethodImpl(MethodImplOptions.AggressiveInlining)]
     public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2>(TTarget? instance, ref TArg1? arg1, ref TArg2? arg2)
     {
-        if (IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
+        if (CanExecuteCallTargetIntegration<TIntegration>() && IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
         {
             IntegrationOptions<TIntegration, TTarget>.RecordTelemetry();
             return BeginMethodHandler<TIntegration, TTarget, TArg1, TArg2>.Invoke(instance, ref arg1, ref arg2);
@@ -330,7 +385,7 @@ public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2>(T
     [MethodImpl(MethodImplOptions.AggressiveInlining)]
     public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2, TArg3>(TTarget? instance, ref TArg1? arg1, ref TArg2? arg2, ref TArg3? arg3)
     {
-        if (IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
+        if (CanExecuteCallTargetIntegration<TIntegration>() && IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
         {
             IntegrationOptions<TIntegration, TTarget>.RecordTelemetry();
             return BeginMethodHandler<TIntegration, TTarget, TArg1, TArg2, TArg3>.Invoke(instance, ref arg1, ref arg2, ref arg3);
@@ -357,7 +412,7 @@ public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2, T
     [MethodImpl(MethodImplOptions.AggressiveInlining)]
     public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2, TArg3, TArg4>(TTarget? instance, ref TArg1? arg1, ref TArg2? arg2, ref TArg3? arg3, ref TArg4? arg4)
     {
-        if (IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
+        if (CanExecuteCallTargetIntegration<TIntegration>() && IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
         {
             IntegrationOptions<TIntegration, TTarget>.RecordTelemetry();
             return BeginMethodHandler<TIntegration, TTarget, TArg1, TArg2, TArg3, TArg4>.Invoke(instance, ref arg1, ref arg2, ref arg3, ref arg4);
@@ -386,7 +441,7 @@ public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2, T
     [MethodImpl(MethodImplOptions.AggressiveInlining)]
     public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2, TArg3, TArg4, TArg5>(TTarget? instance, ref TArg1? arg1, ref TArg2? arg2, ref TArg3? arg3, ref TArg4? arg4, ref TArg5? arg5)
     {
-        if (IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
+        if (CanExecuteCallTargetIntegration<TIntegration>() && IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
         {
             IntegrationOptions<TIntegration, TTarget>.RecordTelemetry();
             return BeginMethodHandler<TIntegration, TTarget, TArg1, TArg2, TArg3, TArg4, TArg5>.Invoke(instance, ref arg1, ref arg2, ref arg3, ref arg4, ref arg5);
@@ -417,7 +472,7 @@ public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2, T
     [MethodImpl(MethodImplOptions.AggressiveInlining)]
     public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2, TArg3, TArg4, TArg5, TArg6>(TTarget? instance, ref TArg1? arg1, ref TArg2? arg2, ref TArg3? arg3, ref TArg4? arg4, ref TArg5? arg5, ref TArg6? arg6)
     {
-        if (IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
+        if (CanExecuteCallTargetIntegration<TIntegration>() && IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
         {
             IntegrationOptions<TIntegration, TTarget>.RecordTelemetry();
             return BeginMethodHandler<TIntegration, TTarget, TArg1, TArg2, TArg3, TArg4, TArg5, TArg6>.Invoke(instance, ref arg1, ref arg2, ref arg3, ref arg4, ref arg5, ref arg6);
@@ -450,7 +505,7 @@ public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2, T
     [MethodImpl(MethodImplOptions.AggressiveInlining)]
     public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2, TArg3, TArg4, TArg5, TArg6, TArg7>(TTarget? instance, ref TArg1? arg1, ref TArg2? arg2, ref TArg3? arg3, ref TArg4? arg4, ref TArg5? arg5, ref TArg6? arg6, ref TArg7? arg7)
     {
-        if (IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
+        if (CanExecuteCallTargetIntegration<TIntegration>() && IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
         {
             IntegrationOptions<TIntegration, TTarget>.RecordTelemetry();
             return BeginMethodHandler<TIntegration, TTarget, TArg1, TArg2, TArg3, TArg4, TArg5, TArg6, TArg7>.Invoke(instance, ref arg1, ref arg2, ref arg3, ref arg4, ref arg5, ref arg6, ref arg7);
@@ -485,7 +540,7 @@ public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2, T
     [MethodImpl(MethodImplOptions.AggressiveInlining)]
     public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2, TArg3, TArg4, TArg5, TArg6, TArg7, TArg8>(TTarget? instance, ref TArg1? arg1, ref TArg2? arg2, ref TArg3? arg3, ref TArg4? arg4, ref TArg5? arg5, ref TArg6? arg6, ref TArg7? arg7, ref TArg8? arg8)
     {
-        if (IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
+        if (CanExecuteCallTargetIntegration<TIntegration>() && IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
         {
             IntegrationOptions<TIntegration, TTarget>.RecordTelemetry();
             return BeginMethodHandler<TIntegration, TTarget, TArg1, TArg2, TArg3, TArg4, TArg5, TArg6, TArg7, TArg8>.Invoke(instance, ref arg1, ref arg2, ref arg3, ref arg4, ref arg5, ref arg6, ref arg7, ref arg8);
@@ -505,7 +560,7 @@ public static CallTargetState BeginMethod<TIntegration, TTarget, TArg1, TArg2, T
     [MethodImpl(MethodImplOptions.AggressiveInlining)]
     public static CallTargetState BeginMethod<TIntegration, TTarget>(TTarget? instance, object[] arguments)
     {
-        if (IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
+        if (CanExecuteCallTargetIntegration<TIntegration>() && IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
         {
             IntegrationOptions<TIntegration, TTarget>.RecordTelemetry();
             return BeginMethodSlowHandler<TIntegration, TTarget>.Invoke(instance, arguments);
@@ -526,7 +581,7 @@ public static CallTargetState BeginMethod<TIntegration, TTarget>(TTarget? instan
     [MethodImpl(MethodImplOptions.AggressiveInlining)]
     public static CallTargetReturn EndMethod<TIntegration, TTarget>(TTarget? instance, Exception? exception, CallTargetState state)
     {
-        if (IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
+        if (CanExecuteCallTargetIntegration<TIntegration>() && IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
         {
             IntegrationOptions<TIntegration, TTarget>.RecordTelemetry();
             EndMethodHandler<TIntegration, TTarget>.Invoke(instance, exception, in state);
@@ -549,7 +604,7 @@ public static CallTargetReturn EndMethod<TIntegration, TTarget>(TTarget? instanc
     [MethodImpl(MethodImplOptions.AggressiveInlining)]
     public static CallTargetReturn<TReturn> EndMethod<TIntegration, TTarget, TReturn>(TTarget? instance, TReturn? returnValue, Exception? exception, CallTargetState state)
     {
-        if (IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
+        if (CanExecuteCallTargetIntegration<TIntegration>() && IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
         {
             IntegrationOptions<TIntegration, TTarget>.RecordTelemetry();
             var result = EndMethodHandler<TIntegration, TTarget, TReturn>.Invoke(instance, returnValue, exception, in state);
@@ -571,7 +626,7 @@ public static CallTargetReturn<TReturn> EndMethod<TIntegration, TTarget, TReturn
     [MethodImpl(MethodImplOptions.AggressiveInlining)]
     public static CallTargetReturn EndMethod<TIntegration, TTarget>(TTarget? instance, Exception? exception, in CallTargetState state)
     {
-        if (IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
+        if (CanExecuteCallTargetIntegration<TIntegration>() && IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
         {
             IntegrationOptions<TIntegration, TTarget>.RecordTelemetry();
             return EndMethodHandler<TIntegration, TTarget>.Invoke(instance, exception, in state);
@@ -594,7 +649,7 @@ public static CallTargetReturn EndMethod<TIntegration, TTarget>(TTarget? instanc
     [MethodImpl(MethodImplOptions.AggressiveInlining)]
     public static CallTargetReturn<TReturn> EndMethod<TIntegration, TTarget, TReturn>(TTarget? instance, TReturn? returnValue, Exception? exception, in CallTargetState state)
     {
-        if (IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
+        if (CanExecuteCallTargetIntegration<TIntegration>() && IntegrationOptions<TIntegration, TTarget>.IsIntegrationEnabled)
         {
             IntegrationOptions<TIntegration, TTarget>.RecordTelemetry();
             return EndMethodHandler<TIntegration, TTarget, TReturn>.Invoke(instance, returnValue, exception, in state);
@@ -612,7 +667,15 @@ public static CallTargetReturn<TReturn> EndMethod<TIntegration, TTarget, TReturn
     [MethodImpl(MethodImplOptions.AggressiveInlining)]
     public static void LogException<TIntegration, TTarget>(Exception exception)
     {
-        IntegrationOptions<TIntegration, TTarget>.LogException(exception);
+        // Not calling CanExecuteCallTargetIntegration because that allows execution
+        // in some scenarios that we definitely _shouldn't_ be running here, so
+        // strictly checking _isIisPreStartInitComplete instead.
+#if NETFRAMEWORK
+        if (_isIisPreStartInitComplete)
+#endif
+        {
+            IntegrationOptions<TIntegration, TTarget>.LogException(exception);
+        }
     }
 
     /// <summary>
@@ -634,4 +697,29 @@ public static unsafe CallTargetRefStruct CreateRefStruct(void* refStructPointer,
     {
         return CallTargetRefStruct.Create(refStructPointer, refStructTypeHandle);
     }
+
+#if NETFRAMEWORK
+    private static bool CanExecuteCallTargetIntegration<TIntegration>([CallerMemberName] string callerName = null!)
+    {
+        if (_isIisPreStartInitComplete)
+        {
+            return true;
+        }
+
+        var boolState = AppDomain.CurrentDomain.GetData(NamedSlotName);
+        _isIisPreStartInitComplete = boolState is false;
+
+        // We _have_ to allow the HttpModule_Integration invocation through, even if we're in the Iis PreStart phase.
+        // That integration is specifically designed to run in this phase. We considered other options
+        // such as moving it to Instrumentation.Initialise, or rewriting directly with the profiling API
+        // but this was the simplest, easiest, and safest approach we could see generally.
+        var returnValue = _isIisPreStartInitComplete || typeof(TIntegration) == typeof(HttpModule_Integration);
+        return returnValue;
+    }
+
+#else
+    // Compiler should inline this out of the condition checks completely
+    [MethodImpl(MethodImplOptions.AggressiveInlining)]
+    private static bool CanExecuteCallTargetIntegration<TIntegration>() => true;
+#endif
 }