Whew. Okay, so we tried a 6-player variant this evening based on the feedback and ideas collected here. It...didn't go very well for our heroes.
To start, we went with 5 hero players against one villain player. On the villain player's turn, he could either:
a) Draw 3 cards, placing one on the bottom of his deck, one in his hand, and one into play.
b) Play a card from his hand.
After 3 heroes had gone, the villain would also get to immediately flip the top villain card. If it was a One-Shot or Ongoing, it would take place immediately. If it was a minion/villain target, it would enter play but not act until the villain's actual turn.
Any card that prevented the villain deck from playing cards affected both occasions, essentially preventing two plays.
Environment deck played as normal at all times.
For the first two games, all minions/drones/etc. also received one extra hit point.
Game 1--Omnitron in the Tomb of Anubis. Heroes: Nightmist, AZ (Wrath), Tachyon (Leader), Tempest, Wraith
Two sets of Sedative Flechettes and two Technological Singularities spelled doom for this group. Omnitron had approximately 40 hp left before the last Flechettes finished off the heroes. It didn't help that I also pulled both Electro-Explosives within 3 turns, which the heroes handled fairly well. Tachyon got a fantastic draw on this game, pulling all three of her damage negating cards in the first 3 turns, effectively preventing huge amounts of damage at the game's outset.
Game 2--Baron Blade in Megalopolis. Heroes: Argent Adept, AZ, Legacy (Old Man), Tempest, Wraith
This one wasn't even close. Blade got out three Hasten Dooms, all three Mobile Defense Platforms, and his Backlash Field. By the time the Heroes could actually function, the Baron was 2 cards away from pulling the moon into the Earth, with a Platform still in play. No chance, whatsoever.
Game 3--Warlord Voss in Insula Primalis. Heroes: Argent Adept, Legacy (Old Man), Tachyon (Leader), Ra, Nightmist
We dropped the minion rule after game 2, figuring that it would make Voss a little easier. And, true enough, it did. It also helped that my group--which usually picks heroes based on their current whims ("I played a buff-bot last time; I want a damage dealer this game.)--decided to make a balanced, well-rounded team. The start of their game was not aided by the Prescence of a Gene-Bound Guard in the opening flop, and a pull of the flagship soon after. AA managed to blow up the flagship at the cost of an instrument, and a well-timed Oblivion cleared the field of minions. Unfortunately, a second flagship and Voss's fearsome damage resulted in a tpk by round 5.
General consensus around my table was that the additional flop partway through the Hero turns was what really imbalanced the game. Villains could simply output damage too fast for Heroes to keep up, particularly when the villain has access to ongoing/equipment destruction. My players had few disagreements in terms of the villain deck mechanic itself--they still put a high value on limiting my options, and potentially removing dire cards.
Adding an intellect to the villain deck definitely changes how its played. The instant you have options, a whole new world of difficulty opens up for the hero players, as the villain player will likely build at least 1 turn ahead, planning out card plays to have the most impact, rather than randomly.
My group is still interested in the challenge offered by a villain player, and wants to give it another go, after some refinement. I believe that the extra hp for minions would make an excellent replacement for the extra villain card, while easing up on the overall pain. I'll ideally I've this a run sometime in the near future and see how it goes!
I would definitely NOT suggest running a human villain on advanced mode, though! It's pain enough to have an evil mastermind behind the cards, much less mechanical advantages as well!