Let's see...excluding DLC, the only game I've ever gotten all achievements/trophies on is Oblivion. I essentially did the same with Fallout 3, but I didn't feel like going back and getting the ones for hitting certain levels with different karma levels.
In a broader sense, I got 100% personas/social links in Persona 3 Portable, I did just about everything in most of the GBA/DS Castlevanias, I did all sidequests/Riddler Challenges in Arkham Asylum/City (ignored the combat/stealth challenges though), got everything in Banjo Tooie, and was 3 blue coins from getting everything in Super Mario Sunshine before my save corrupted.
The hardest I ever did was getting every single gap in Tony Hawk Underground. Still not sure if it's possible to do without moon gravity