I have to say Doc Ock, but
Willem Dafoe Green Goblin is a close second. I'm actually not a big fan of the Doc Ock from the comics because he was the typical "crazy genius" type, but Spider-Man 2 fleshed him out a little more. I also like him in Superior Spider-Man (there, I said it). Green Goblin is my favorite Spider-Man villain, but the costume brings Gobby down in the first Spider-Man villain. I also don't like how they shafted Gwen Stacy's death, but I can understand why they did.
I liked the special effects of Sandman, but I didn't like what they did to his character by having him be the one who killed Uncle Ben. Also, the "sympathetic" approach they tried to take with him just didn't work. And we'll just skip Venom and Harry Osborn altogether.
As for the Lizard... I really don't like how he was portrayed. I like how his look paid homage to Steve Ditko's Lizard design, but I don't like how they left out his family and gave him a laughably bad plan. I know there is a deleted scene where Dr. Connors talks to his son, but if it ain't in the movie, it ain't in the movie!
Green Goblin and Doc Ock. Both were portrayed quite well, and Ock actually exceeded his comic book counterpart. Green Goblin was definitely the more threatening of the two. I liked both, but if I was the director I likely wouldnt have wasted a whole movie with Ock as the main villain.
I think that in TASM, Lizard was the hero and Peter was the villain. He was just trying to put new york out of the misery of seeing Andrew garfield as spiderman and watching a great comic hero burn. Nice one Garfield. You killed new york's hope of ever seeing a good a list movie with no stupidity.