Do New Vegas; but mod the bejeezus out of it. Have a look around the NV Nexus and decide on some good mods. I'm not at home now so can't give a list; but looks for things that:
Brutally increase the efficacy of firearms. Bullets hurt. No matter how tough you are, even the lowliest of firearms can kill on a single shot. You'll be ducking for cover like crazy when you hear firearms in the distance. And while you're there, increase damage for all weaponry. A knife in the liver doesn't tickle any more than a bullet to the spleen.
Strip ammunition out of the game. That is; this is a wasteland which has seen a few hundred years of anarchy. The only thing more valuable than functional ammo is clean water. You'll be relying on knives and old pipes quite a lot now. The good mods of course mean that enemies will expend their ammunition as well - no more endless ammunition clips on NPCs.
Zombify the ghouls. Feral ghouls no longer run, and require head shots to kill. They also spawn in much larger numbers. A minor annoyance becomes a threat to all survivors in the wasteland.
Survivalism it up. There's a couple of good mods that deal with the dangers of sleep/water/food deprivation; others make radiation something that is actually quite likely to kill you if you're not careful, and others make medical bits and pieces absolutely essential supplies (instead of just being world clutter, medical braces/tubing/crutches/blood bags/painkillers become absoultely critical supplies to hoard in your wasteland shack).
I'm a closet nutjob survivalist, so I approach Fallout as a means to test my hoarding/scavenging/hiding/surviving abilities. I remember playing FO3 once and about 4 weeks had passed - I was in absolute dire straights. I had been sheltering in the facility underneath the Anchorage Memorial for three days - a radioactive rainstorm had persisted for the past 3 days. I was running dangerously low on supplies - if I didn't get out and find some food and water, I was entirely liable to die, stranded on the edge of DC. Long story short, it didn't stop raining. I had to make a desperate dash for the Russian guy with the two sex slaves. Usually, there's not really any point to killing them. But when you're starving and dying of thirst, and suffering the advanced effects of radiation sickness, it opens up a new realm of RP opportunities. There was food, and water, and medicine in that hotel, so I was presented with two choices: whoring, or murder. Let's just say my karma took a hit in that hotel. And the three bodies were disposed of. Tastily. >

Cannibalism, as a survival tool, is remarkably useful. That's why so many disaster stories and games feature cannibalism.