diff --git a/synapse/http/proxyagent.py b/synapse/http/proxyagent.py
index 8de1088e10c3..f0c6756bb713 100644
--- a/synapse/http/proxyagent.py
+++ b/synapse/http/proxyagent.py
@@ -24,7 +24,11 @@
 from zope.interface import implementer
 
 from twisted.internet import defer
-from twisted.internet.endpoints import HostnameEndpoint, wrapClientTLS
+from twisted.internet.endpoints import (
+    HostnameEndpoint,
+    UNIXClientEndpoint,
+    wrapClientTLS,
+)
 from twisted.internet.interfaces import (
     IProtocol,
     IProtocolFactory,
@@ -42,7 +46,11 @@
 from twisted.web.http_headers import Headers
 from twisted.web.iweb import IAgent, IBodyProducer, IPolicyForHTTPS, IResponse
 
-from synapse.config.workers import InstanceLocationConfig
+from synapse.config.workers import (
+    InstanceLocationConfig,
+    InstanceTcpLocationConfig,
+    InstanceUnixLocationConfig,
+)
 from synapse.http import redact_uri
 from synapse.http.connectproxyclient import HTTPConnectProxyEndpoint, ProxyCredentials
 from synapse.logging.context import run_in_background
@@ -142,20 +150,34 @@ def __init__(
 
         self._federation_proxy_endpoint: Optional[IStreamClientEndpoint] = None
         if federation_proxies:
-            endpoints = []
+            endpoints: List[IStreamClientEndpoint] = []
             for federation_proxy in federation_proxies:
-                endpoint = HostnameEndpoint(
-                    self.proxy_reactor,
-                    federation_proxy.host,
-                    federation_proxy.port,
-                )
-
-                if federation_proxy.tls:
-                    tls_connection_creator = self._policy_for_https.creatorForNetloc(
-                        federation_proxy.host.encode("utf-8"),
+                endpoint: IStreamClientEndpoint
+                if isinstance(federation_proxy, InstanceTcpLocationConfig):
+                    endpoint = HostnameEndpoint(
+                        self.proxy_reactor,
+                        federation_proxy.host,
                         federation_proxy.port,
                     )
-                    endpoint = wrapClientTLS(tls_connection_creator, endpoint)
+                    if federation_proxy.tls:
+                        tls_connection_creator = (
+                            self._policy_for_https.creatorForNetloc(
+                                federation_proxy.host,
+                                federation_proxy.port,
+                            )
+                        )
+                        endpoint = wrapClientTLS(tls_connection_creator, endpoint)
+
+                elif isinstance(federation_proxy, InstanceUnixLocationConfig):
+                    endpoint = UNIXClientEndpoint(
+                        self.proxy_reactor, federation_proxy.path
+                    )
+
+                else:
+                    # It is supremely unlikely we ever hit this
+                    raise SchemeNotSupported(
+                        f"Unknown type of Endpoint requested, check {federation_proxy}"
+                    )
 
                 endpoints.append(endpoint)