Spider-Man himself mutating into a hideous, vicious, terrifying man-spider. And later on, the Vulture, with his youth-draining tech, sucking the youth out of people, lastly Spider-Man... and also absorbing his mutating DNA, causing him to sporadically turn into the Man-Spider himself, but retaining his full intelligence and power of speech, and then later seemingly permanently being trapped as the Man-Spider for the rest of his life. Sure, he brought it on himself, but still. Fortunately for him, he is cured by an off-screen plot device...
There is something subtly disturbing about the storylines involving Hydro-Man — his sheer relentlessness combined with the fact that anything Peter does to him will only stall him for a few minutes is bad enough, but then he dies because Mary-Jane tricks him into spending so long away from water that he evaporates, and Spider-Man just has to say that water is so common that it's possible he'll come back one day, which means a) it's possible that he's still sentient in his evaporated form, b) he might return having learned from that defeat, rendering him genuinely impossible to get rid of. And then he does come back. And it turns out that he and the current Mary-Jane are both clones of the originals, and they both just disintegrate into water.
Spider-Man's reaction to him watching Mary Jane fall into one of the portals, presumably to her death. He is out to KILL the Goblin. It's not black suit Spidey, being controlled and crossing the lines. It's Peter Parker, having watched the woman he loves die, and wanting to kill the man responsible.
