diff --git a/Lib/test/test_urllib2net.py b/Lib/test/test_urllib2net.py
index 5da41c37bbfb8e..d8d882b2d33589 100644
--- a/Lib/test/test_urllib2net.py
+++ b/Lib/test/test_urllib2net.py
@@ -134,7 +134,9 @@ def setUp(self):
     # They do sometimes catch some major disasters, though.
 
     def test_ftp(self):
+        # Testing the same URL twice exercises the caching in CacheFTPHandler
         urls = [
+            'ftp://www.pythontest.net/README',
             'ftp://www.pythontest.net/README',
             ('ftp://www.pythontest.net/non-existent-file',
              None, urllib.error.URLError),
diff --git a/Lib/urllib/request.py b/Lib/urllib/request.py
index 73ad0127ecc969..24911bb0190b8e 100644
--- a/Lib/urllib/request.py
+++ b/Lib/urllib/request.py
@@ -2469,7 +2469,13 @@ def retrfile(self, file, type):
         return (ftpobj, retrlen)
 
     def endtransfer(self):
+        if not self.busy:
+            return
         self.busy = 0
+        try:
+            self.ftp.voidresp()
+        except ftperrors():
+            pass
 
     def close(self):
         self.keepalive = False
diff --git a/Misc/NEWS.d/next/Library/2023-04-22-22-14-09.gh-issue-81403.zVz9Td.rst b/Misc/NEWS.d/next/Library/2023-04-22-22-14-09.gh-issue-81403.zVz9Td.rst
new file mode 100644
index 00000000000000..6adb71f7677229
--- /dev/null
+++ b/Misc/NEWS.d/next/Library/2023-04-22-22-14-09.gh-issue-81403.zVz9Td.rst
@@ -0,0 +1,3 @@
+:class:`urllib.request.CacheFTPHandler` no longer raises :class:`URLError`
+if a cached FTP instance is reused. ftplib's endtransfer method calls
+voidresp to drain the connection to handle FTP instance reuse properly.