diff --git a/CommunityToolkit.Mvvm/Messaging/Internals/System/Gen2GcCallback.cs b/CommunityToolkit.Mvvm/Messaging/Internals/System/Gen2GcCallback.cs
index c8a07e05c..be54bb163 100644
--- a/CommunityToolkit.Mvvm/Messaging/Internals/System/Gen2GcCallback.cs
+++ b/CommunityToolkit.Mvvm/Messaging/Internals/System/Gen2GcCallback.cs
@@ -41,6 +41,16 @@ private Gen2GcCallback(Action<object> callback, object target)
     /// <param name="target">The target object to pass as argument to <paramref name="callback"/>.</param>
     public static void Register(Action<object> callback, object target)
     {
+#if NETSTANDARD2_0
+        if (RuntimeInformation.FrameworkDescription.StartsWith(".NET Framework"))
+        {
+            // On .NET Framework using a GC callback causes issues with app domain unloading,
+            // so the callback is not registered if that runtime is detected and just ignored.
+            // Users on .NET Framework will have to manually trim the messenger, if they'd like.
+            return;
+        }
+#endif
+
         _ = new Gen2GcCallback(callback, target);
     }
 
diff --git a/tests/CommunityToolkit.Mvvm.UnitTests/Test_Messenger.cs b/tests/CommunityToolkit.Mvvm.UnitTests/Test_Messenger.cs
index 14a9a593e..9c298b8be 100644
--- a/tests/CommunityToolkit.Mvvm.UnitTests/Test_Messenger.cs
+++ b/tests/CommunityToolkit.Mvvm.UnitTests/Test_Messenger.cs
@@ -468,6 +468,7 @@ void Test()
         Assert.IsTrue(messenger.IsRegistered<MessageA>(recipient));
     }
 
+#if NETCOREAPP // Auto-trimming is disabled on .NET Framework
     [TestCategory("Mvvm")]
     [TestMethod]
     public void Test_Messenger_AutoCleanup()
@@ -515,6 +516,7 @@ void Test()
 
         GC.KeepAlive(messenger);
     }
+#endif
 
     [TestCategory("Mvvm")]
     [TestMethod]