We fade in after the usual art flashback on the last movie - we fade in to Mary Jane and we find out that she's quit the stage to pursue a career in modelling and that the first shot in the film with the first lines by Peter Parker is a shot of M.J in her new modelling poster which Peter stares at before he goes in to the studio that takes her photos to see her.
He's brought her flowers, they kiss, and romance prevails in the story. Peter still has some doubts about the safety of the two of them engaging into a relationship and meets and befriends (in a way, his "new" best friend) astronaut Edward Brock (Topher Grace) who is the quite the comedian, often upsetting M.J.
Meanwhile, M.J works to reconcile Peter's relationship with Harry Osborne who does not yet reveal that he's found out the secret about his father. Harry takes on more heavier drinking while putting on a false reconciliation with Peter by throwing a party for the both of them, there he meets Topher, I mean Eddie. Eddie says at one point in the film, "I know I'm not a day older than you Peter... but I'm beginning to feel the astronaut life is weighing far too much for me. I'm thinking about retiring and maybe then you could find me a job as a reporter for the Daily Bugle" which Peter happily looks forward to. Harry takes notice of the bond established between Eddie and Peter and begins feeling jealous - at the same time his schizophrenia about his father returning starts getting a stronger hold on him on a par with his alcoholism.
Edward goes to M.J's apartment to look for Peter (whose off saving people from Sandman - whose not yet Sandman, just a common criminal by the name of Flint Marko) and M.J covers up for Peter. Eddie decides to leave his gift to Peter for saving him the other day (in a scene where Peter Parker (not Spider-man) saves him from a few Muggers. This scene is highly significant because after Peter saves Eddie, Ed comments on how not all of us have the innocence of comedy in ourselves - but to believe in that innocence, is a dream of mine) M.J asks Edward why can't he give it to Peter himself and Ed says he's got this huge expedition in space - his final "lift off" and he'll stay grounded for ever.
The gift happens to be an access pass to the Space station that corresponds to the transmission between NASA and the spacecrafts in orbit - this way Pete can contact Edward. Meanwhile, Flint Marko - takes on his pedestrian counter-part as William Baker - who works to scam Oscorp. Pete gives Harry some helpful intellectual strategies on how to counter Baker's plot to ruin him - Harry thanks him and they have a small sentimental talk as friends about why he killed his father.
Harry asks Peter if he knew all along, and Peter says he didn't - not till the end. Peter then tries to reconcile any past issues between Harry and his father but Harry says the real Norman Osborne died regretting Peter Parker wasn't his son. Harry quickly apologizes for saying that by using his typsy-ness as an excuse. Peter understands Harry envys the life Peter's living, but Peter tells he would rather live a life without so many risks. Harry reassures he's always got him. Meanwhile, William Baker breaks into Harry's office later and finds the Goblin lair - he is directed by the Green Goblin in the form of Norman Osborne - Harry wasn't schizophrenic after all - to put some of the Performance Enhancing Syrum into Harry's alcoholic beverages - in return, Baker gets the location of a place where he can rob himself to riches. Peter and M.J go to the Space Station and they talk to Eddie from space.
This is the last friendly conversation Peter and Eddie ever engage in as they cheer off their happy anniversary until something goes horribly wrong - a substance they've gathered from one of the moon rocks has caused a combustion in the shuttle engine.