The dual .50 caliber pistols in True Crime: New York City. Those things were great, they could take a grown man's head off in one shot. Two shots to the body could shred them to pieces. They where never actually identified as anything other than .50 caliber pistols, but they looked like Desert Eagles. I loved those guns, I still get a warm feeling just thinking about them.
Not sure it counts, but the knife from GTA: San Andreas, a one hit stealth kill, mmmmmmmmmmmm. But then it got nerfed in GTA:IV and now it's shit.