Green Goblin (Norman Osborn)
Doctor Octopus (Otto Octavius)
Venom (Eddie Brock)
...
...
Hmmm... fourth is tricky tricky...
- Kraven: Being an original Sinister 6er, Kraven's Last Hunt
- Lizard: The Hyde of great power and unfettered science, a dark reflection and cautionary tale
- Kingpin: A constant presence in the background of a lot of heavier Spider-periods, though definitely Daredevil's #1 for Rushmore
- Jackal: Behind the Clone Saga, another Lizard-esque caution
- Mysterio: A secondary villain until he became much more influential and manipulative with the tangled web of multiversal spiders
And I don't have enough knowledge of more modern villains and impactful they are like Mr. Negative, Judas Traveller, Mephisto post-OMD, or if Spot's gotten a lot more outsize influence aince the brilliant Across the Spider-Verse (ooh, Miguel... and there's Prowler if we fold in Miles)...
Actually, with how often she can flip the script on Spidey as a self-interested third-party...
Green Goblin
Doctor Octopus
Venom
Black Cat
"In my headcanon, some staffer saw Trump pull out his phone and start typing so they just Terry Tate Office Linebacker'd him out of his shoes." - FFD