~Bring back Doctor and First-aid and associated kits and doctor bags. Only make them more useful than in FO1 and 2 considering that if you are using your doctor or first-aid skill with your bare hands, it won't do much.
~Pain should play a role in the character's, and every other NPC's and certain critters' performance. There should be a certain "pain threshold" depending on Endurance.
~Make limbs easier to cripple and much more difficult to treat, even with a high doctor skill and correct supplies... perhaps make it so certain times, the injury is so severe that the player must live with it for a while, even if treated 100% by a physician or by the character themselves with an extremely high doctor skill.
~Like everyone else said, poisoning in various ways, but different antidotes unlike in FO1 and 2 it was always the radscorpion antidote, used for any type of poisoning other than only radscorpions.
~Diseases and real, noticeable complications. Even colds, and other minor health complications to worry about too, and everything I mentioned should affect every human NPC possibly, and perhaps unique diseases that affect other races like ghouls and super mutants.
~No invulernability during VATS.
~What everyone else said about there not being so many hostile encounters and critters and such...
~More random items that are useful, not just a bunch of toy cars and lunchboxes and things like that everywhere that are only for these homemade weapons. Not as many intact computers and things like that, sitting in the middle of rubble and burned out furniture and stuff... on that note, if you hack a computer and it says "deactivate turret system", the entire turret system in that building/area should be deactivated, not just that SINGLE turret around the corner. Etcetera.