So, just out of my own curiosity, what do you all consider the worst card for a given villain to flop on the first turn? The one that comes down and immediately signals a game that's going to be, at best, hard as hell on you and at worst, all but unwinnable?
For me, the first that comes to mind is Profane Summons with Apostate. The first time we played against him, he flopped that and pulled out the Runes of Malediction, Tome of the Unknowable, and the Orb of Delirium -- we won, but it was painful starting out since we all needed cards to do anything.
The second is Ravage from Plague Rat -- having four out of five heroes punching themselves in the face from the start before you have the cards out to mitigate it is rough.
The classic combo is for Citizen Dawn to start with Citizens Sweat & Tears, and follow that with a Blinding Blast. Congratulations! Now nobody has any cards in hand, and you'll be losing your card draws every round. Have fun!
For the Chairman, it's hard to match a Contract + Enforcer opening.
For the Matriarch, a double Cohort opening means you're probably screwed, especially if you're playing Advanced.
For Baron Blade, Backlash Field is probably the worst card unless you have ongoing destruction on hand.
Raiding Party is probably the nastiest La Capitan opening.
It's probably a toss up which of Voss's ships is the worse opener.
Omnitron flipping a turn 1 Electro-Pulse Explosive. Bonus points if it’s Cosmitron. Extra-special screwed with fudge on top if Cosmitron pulls both of them.
Not quite as devastating, but I had a game against The Dreamer on Advanced where she opened with both Dark Heroes and both Tooth Fairies. In a shocking twist, we lost.
I had a game against Iron Legacy where he started with both Galvanized, Demorilizing presence and Vigilence. Needless to say, nobody survived past the second round because taking 5 damage a play hurts a lot
Any cards that limit what you can do at the start of the game is always a pain, so Crushing Cage, Vengeance Blade's card that keeps your from using extra powers or playing extra cards, things like that. It's not really difficult so much as kind of annoying.
Citizen dawn with hammer and anvil. Truth and sweat and first play is blood. Two cards gone no damage to anyone but truth and truth has reduction 2 . That is my least favorite situation
I was gonna say the "Sweat and Tears to start off and then Blinding Blast as the played card" thing as that's happened to me, but I've been beaten to it ;).
Villains that can chain stuff (eg Hasten Doom, Primeval Eruption) can be a pain if they manage that from the start, though.
Ambuscade is usually a pushover, but not if he gets charged attacks out with a few sonic mines first turn. If the environment blows any of them up, the heroes each take tons of damage.
If Kaarga comes into play first round and gets the title that lets her play a card the first time each turn she's damaged, you're going to have a bad time. (haven't seen that on turn one, it was turn two instead IIRC)