Hardcore Mass Effect Series:
-Shepard can die. Permanently. You must continue as one of your squadmates.
-Your squadmates can die permanently.
-No more black and white decisions. (And realistic consequences of your actions) Meaning making someone love you just got a whole lot tougher.
-You can all die on the suicide mission. When you load Mass Effect 3, you get a message to the effect of "Hahaha, no. You died. Deal with it." And the game gives a message "Insert Mass Effect 2, Disc 1"
-STD's. That'd add a bit of !!FUN!! to the dating game. Especially since the !! is the burning feeling Shepard gets when he pees now.
-PTSD. Oh no, Shepard's too emotionally tormented by the tough, non morally aligned decisions he's made? Who'll stop the Reapers now?
-Medi-gel is no longer omnipotent, and your enemies can use it too.
-Shepard can only carry two weapons, just like his squadmates.
-Shepard has the same limits on the number of powers he can use as his squadmates.
-You only have a set amount of game time in Mass Effect 3. The Reapers invade a new planet every time a certain amount of game time passes. ACTUALLY, SCRATCH THAT.
-A time system like Fallout One. Once X amount of time has passed, fuck you, the Reapers own the Milky Way. Every ingame (week, month?) the Reapers invade a new planet. You can slightly delay that by doing certain missions, which will certainly be tougher due to...
-Good AI. <--This could make any game hardcore.
^ This would be a hardcore, yet fun (imo) game.