Bizarrely enough, Traveller.
I've played it loads, love the background to death, but really, I mean REALLY, have a problem with the fact that Traveller space is FLAT. I mean, you're in a starship, and you can fly forwards, backwards, left and right - but not up or down!
Traveller space is 1 parsec thick... It's just such a massively illogical non-sequitur that it just blows the rest of it out of the water for me. Plus you can't use all that nifty stellar cartography software out there...
Then again - Arcanum and the Bestiary. Loved all the setting material, but something about it never quite gelled for me. Shades of Conan, which was absolutely great - but then with all these Tolkien elves in full-plate armour popping up. Shattered the illusion.
Cheers,
Sarah