For games where counting completions is easy, Metal Gear Solid 2 is probably number one, followed by Metal Gear Solid 4. That said, I played MGS4 like seven times the in what was probably a few weeks when it was released and have touched it only a few times after that, so it gets kind of an unfair advantage.
Grim Dawn and Titan Quest are some of the more ambiguous games. I've completed those games probably more times than MGS2 and MGS4... if we count completions on different difficulty levels. However, because replaying the game on a different difficulty level with the same character is a natural progression in those games, I always feel uneasy counting different difficulty levels as different completions.
Other honorable mentions would probably include Half-Life 2 and the first episode of the original Doom as well (curse you, Bethesda, for releasing another game with the same name!).
