Smash Bros Melee.
Last time I checked the statistics (shortly before getting brawl) it had over 700 hours played (almost exclusively 3-4 players). And that's only counting MY savegame, not when we played somewhere else on someone elses console/savegame.
Obvious early pokemon games also.
My Red and Silver savegames each have 200-250 hours on them (glad I never lost those savegames).
The ones afterwards I only played through once, though.
There might have been a few games that also got to the three-digit hour mark (Lufia II for SNES, Secret of Mana for SNES), but I don't remember many of them.
Also I'm not going to count any mmo's I played because I have simply no way of measuring how much time I actually spent playing them over the time that I had an active account there.