diff --git a/changelog.d/6241.bugfix b/changelog.d/6241.bugfix
new file mode 100644
index 000000000000..25109ca4a6a0
--- /dev/null
+++ b/changelog.d/6241.bugfix
@@ -0,0 +1 @@
+Fix error from the Pillow library when uploading RGBA images.
diff --git a/synapse/rest/media/v1/thumbnailer.py b/synapse/rest/media/v1/thumbnailer.py
index 8cf415e29dee..c234ea74212f 100644
--- a/synapse/rest/media/v1/thumbnailer.py
+++ b/synapse/rest/media/v1/thumbnailer.py
@@ -129,5 +129,8 @@ def crop(self, width, height, output_type):
 
     def _encode_image(self, output_image, output_type):
         output_bytes_io = BytesIO()
-        output_image.save(output_bytes_io, self.FORMATS[output_type], quality=80)
+        fmt = self.FORMATS[output_type]
+        if fmt == "JPEG":
+            output_image = output_image.convert("RGB")
+        output_image.save(output_bytes_io, fmt, quality=80)
         return output_bytes_io