Unless you use Qt quick which seems to be the way forward, and what many devs with html/css/js background seem to prefer.
Qt widgets look close to native UIs but the feel isn't always the same, especially when you have to juggle with different platforms (all native widgets differ in subtle ways even when their function is the same).
Pywin32 to call native apis for GUIs sounds very, very painful. I had a few run-ins with pywin32 and COM automation, I don’t think I could bear the thought of developing a full UI with that sort of hacks. At that point, might as well go C# (or IronPython, if it’s still around) and enjoy the VS goodies.
COM might have its issues, but I meant using the win32gui, win32api etc. modules to call the native win32 C API for UI. That's hardly a hack, and perhaps even slightly less painful than doing it from C. (I'm only using it for some fairly small things, though.)