1) Respawn rate of random beast and NPCs.
2) Population density of random NPCs and monsters-affecting caves and bandit camps groupings
3) NPC and Creature abilities-base attributes and skills, frequency of casting and special powers.
4) Good old fashion damage/health ratio
5) Group tactics-Melee get in your face more while range duck and cover, NPC healing one another and conjurers summoning and running like chickens. Also how far people can call for help or how likely they are to run and get it.
6) NPC AI-down potions, heals self, sneak attacks and fire from cover.
You could play the game on standard settings or set it to little or no respawon like Morrowind for those who don not like seeing bandits back in a cave cleared a couple days before. At the other extreme you could turn up population and respawn while increasing your damage and health thus truing it into a near Diablo like hack and slash.
I don't think 1-4 would take too much to implement. 5 and 6 would require more effort, but I feel having more adjustable difficulty options can allow PC, PS3 or Xbox360 players to personalize the game.
What types of difficulty options would you like to see?