Onder andere met: Tobey Maguire (Spider-Man/Peter Parker), Kirsten Dunst (Mary Jane Watson), James Franco (Harry Osborn), Alfred Molina (Doc Ock/Dr. Otto Octavius), Rosemary Harris (May Parker), J.K. Simmons (J. Jonah Jameson), Donna Murphy (Rosalie Octavius), Daniel Gillies (John Jameson), Dylan Baker (Dr. Curt Connors), Bill Nunn (Joseph `Robbie` Robertson), Vanessa Ferlito (Louise), Aasif Mandvi (Mr. Aziz), Willem Dafoe (Green Goblin/Norman Osborn), Cliff Robertson (Ben Parker), Ted Raimi (Hoffman)