During our visit to the National Museum of the American Indian on Friday, one interesting point was made that I hadn't thought about. Everyone knows how, amongst the many awful things that the Europeans did to the Native Americans, one of the worst was the smallpox infestation in the blankets. Europeans, crammed into cities, had lots of experience with deadly diseases (and had provided those diseases the ideal conditions to spread and mutate), and had developed resistances to them. The Native Americans, spread out in small tribes, had neither the diseases nor the resistances to them. The Europeans didn't intend to devastate the "Indians" with disease; they had no idea that they were doing it. But doing so did fit in with the general pattern of how the Europeans treated them.
Because of the differences mentioned above, it was far more likely that the Europeans would bring deadlier diseases. But there's no reason it couldn't've happened the other way around. What if, by chance, the Native Americans happened to carry a disease to which they'd built up a resistance, but which would tear through the unprepared Europeans? Because of their crowded cities and poor sanitation, a disease completely unrelated to the ones they'd dealt with in the past might have ripped through Europe after the first return voyage bringing "Indians" and their artifacts back. If it were deadly enough, and unrelated enough to European diseases, it could have made the Black Plague seem mild by comparison.
This suggests an alternate history I've never seen explored or even proposed. It could go so many different ways. What a rich ground for exploration of story possibilities.