While Gran Turismo may be best driving game I've played (in overall design), I think I'll have to again go with Other.
But which? Fallout, AoE and GTA started major series.
Monkey Island 3 and Wing Commander: Prophecy are good entries of my favorite series.
Further personal favorites include Outlaws and Sid Meier's Gettysburg!
I'll give it to The Curse of Monkey Island, I feel it's hugely underrated.
(Even through I'll have to say Grim Fandango next year.)