Secret Invasion killed Wasp, caused Dark Reign and reminded us how much of a jerk Hank Pym can be (among other things). Civil War divided the superhero community and damaged the world's opinion of superheroes to an extent that is still being seen. Mind you, those are only some of the things the latter events did to change Earth-616, but my point is that they made a significant impact. These were events that made lasting change and involved characters from many different titles. They're big turning points in Marvel history.
These events are all pretty recent, too; being a relative newcomer to the world of comics, I'm somewhat unfamiliar with older events that don't include the X-men. I know that events the Phoenix Saga changed Marvel significantly, but that's almost exclusively an X-men event.
So what event made the most impact?