Who do you consider to be Spidey's main villain? Green Goblin - Responsible for one of the most life altering moments of Peter's life. The death of Gwen Stacy. The mantle of the Goblin corrupted the life of Peter's best friend, Harry. No villain has ever haunted or affected Spider-Man's life quite like GG. Doc Ock - Handed Spidey his first defeat. Which humbled him & made him re-think his approach to crime fighting. Created the Sinister Six, bringing about one of THE toughest physical challenges Spidey has had to date. No other villains can compare. Not even Venom as some symbiote fanboys like to claim.