Why would it be a problem? I suspect not everyone who buys PDFs prints them out in order to play, and if they do, Letter and A4 paper are close enough in size that you'll just have some weird margins. For what it's worth, my own Tales of Space and Magic is typeset on A4, and nobody has complained yet. :P
Of course, that goes for tabletop RPGs. If you're talking card games or some other type of material that requires scissors, you'll need to either leave enough of a margin, thus wasting paper, or else make two versions of the game. And the latter is a big can of worms.