My favorite? The Fantastic Four versus Ultron. I think the homicidal robot could have given Reed a run for his money. Imagine if Ultron subverted HERBIE or Roberta to get intel, then launched an attack that blew apart the Baxter Building. It could be one heck of a battle.

Throwing it open to the Forum, are there any hero/villain swaps you'd like to see? Bear in mind that Dr. Doom has fought most of Marvel's heroes at one point or another.

Ultron versus the FF does make a lot of sense, kind of surprised that didn't happen more often.

The story (for those who don't know) had the depressed super-villain Scorpio (who was Nick Fury's brother), the brand new (android) version of the Zodiac super-villain team, and guest-star Moon Knight, all in a series that previously had two years of Steve Gerber's (wonderful) weirdness which included a healthy dose of Dr. Strange magic, a murderous Elf with a Gun, and the Bozo Cult.

Scorpio himself was last seen in NICK FURY AGENT OF SHIELD and the (original) Zodiac in THE AVENGERS, neither of which seemed at first glance your usual MOON KNIGHT or DEFENDERS foes.  But it practically became THE Defenders story!

The Sandman is another great example, and another character who was practically reinvented (redesigned certainly) whenever he traveled over to FANTASTIC FOUR as a member of the Frightful Four.

Many of the Legion of Super-Heroes' galaxy-spanning villains vs. Green Lantern

Mixing companies a bit--

I'd like to see any of the Fantastic Four's more cosmic enemies go up against Superman

Clayface would be good against Spider-Man or the Defenders

I think I'd rather see the Spectre interact with most of Dr. Strange's otherworldly villains and entities

Marvel's Mr. Hyde would be interesting to see go up against almost anybody at DC

I could go on and on!