Mass Effect is great and all, but are there really no other candidates?
Ugh...now that I'm thinking about it, I actually am having trouble finding a recent game with NPCs that deserve that honor. I guess that's why there aren't many candidates besides the ME crew.
But here's what I got:
1) Arlo (from Hellgate: London). Plays a fixer in a sandbox world (not Hellgate, obviously) who has to pay off his debt or the Powers That Be are going to cut off his thumbs, break his knees, or force him into a fursuit for the rest of his life.
He needs to use his powers of "negotiation" to acquire sales and product all the while fighting his incredibly politically-incorrect personality and gigantic potty mouth.
2) Sierra and/or Larc (from Legend of Mana). I'm actually very interested what role they played in the Deathbringer War and how they got to where they were in Legend of Mana. You see a couple of very brief allusions to the war, but we honestly get close to nothing and know very little of these characters (especially compared to the characters involved in the other two "Major Quests/Stories").
It would be interesting to see how the world fit together before Legend of Mana's "compartmentalization" took over; both geographically and politically.
3) Freya (from FF9): Well...I might renege on this one because:
1) her story is already told and 2) that would mean returning to the Clowntopia that was FF9's universe (which I didn't like). 3) She was a player character (but not a main character; her role was ancillary at best to the main plot).
However, Freya was a great female character in an industry that typically ignores all but the most superficial/cliche' attributes of female characters. I don't even care if she's a rat; she was awesome and actually had a personality and that counts for a lot more.