This would be a very tough group of FOUR to pick, so...
**This is a FIVE-HEADED Mt. Rushmore**
I realize much will depend on if you're a fanboy from the 60s-70s or 80s-90s.
Here are mine: Doctor Doom, Magneto, Galactus, Loki
Other legit candidates: Thanos, Apocalypse, Red Skull, Green Goblin, Doctor Octopus, Juggernaut, Baron Zemo, Ultron, Abomination, Venom, Kang, Bullseye
Personally, I think you'd almost have to do a 'Mount Rushmore of Villains' with six instead of four, and if we did then I'd go with Thanos and Red Skull as my 5/6.
*note that this isn't about the most powerful, but rather the most iconic