diff --git a/source/gui/__init__.py b/source/gui/__init__.py
index 7a4e46e7851..368e537acd5 100644
--- a/source/gui/__init__.py
+++ b/source/gui/__init__.py
@@ -597,6 +597,21 @@ def initialize():
 		raise RuntimeError("GUI already initialized")
 	mainFrame = MainFrame()
 	wx.GetApp().SetTopWindow(mainFrame)
+	# In wxPython >= 4.1,
+	# wx.CallAfter no longer executes callbacks while NVDA's main thread is within apopup menu or message box.
+	# To work around this,
+	# Monkeypatch wx.CallAfter to
+	# post a WM_NULL message to our top-level window after calling the original CallAfter,
+	# which causes wx's event loop to wake up enough to execute the callback.
+	old_wx_CallAfter = wx.CallAfter
+
+	def wx_CallAfter_wrapper(func, *args, **kwargs):
+		old_wx_CallAfter(func, *args, **kwargs)
+		# mainFrame may be None as NVDA could be terminating.
+		topHandle = mainFrame.Handle if mainFrame else None
+		if topHandle:
+			winUser.PostMessage(topHandle, winUser.WM_NULL, 0, 0)
+	wx.CallAfter = wx_CallAfter_wrapper
 
 def terminate():
 	import brailleViewer