Hard to think....since these days, I don't do a lot of multiple run-throughs on games from start to finish...Then again, I never really did...
I have secured ALL endings out of Shadow of Destiny, from start to finish; if I recall, there's 7 or 8 of them in total. Though, the game is around 5-8 hours per playthrough.
I think Morrowind (+ expansions) and Oblivion (+ DLC + expansions) have sucked the most hours out of me -- both each have taken over 150 hours of me, at least! Of course, never did multiple playthroughs ever once on either of those. NEVER.
You know, I'd have to really think on this one, to come up with a true answer...if possible...
EDIT:
I only really been through Deus Ex once. I did do all the endings from Deus Ex; though, I got them from reloading a save at the very final level, before you make the decision of which path to take. Same goes for DX: Invisible War, as well.
You know, I've been played through Tekken 2 and most of MK games with most characters, numerous times. Of course, those can be finished in usually minutes to hours, unlike LONG games.
EDIT #2:
I've been through STALKER once; never finished on my 2nd time through -- and the same goes for many other games, such as Planescape: Torment, Arcanum and Fallout 2.
EDIT #3:
I've been through Vampire: Bloodlines at least two times.