Even without powerful items or synergies, the challenge of Mega Satan (or any other boss) can be skipped by teleporting out of the room.The Wafer is an extremely useful item to receive in this challenge as well.Finally, size-decreasing items, such as Pluto or items that block bullets, such as Trinity Shield will drastically reduce the difficulty of most of Mega Satan's attacks. Having Gnawed Leaf and something that can do damage while not moving, such as Daddy Longlegs, Dead Bird, or Smart Fly, can basically guarantee an eventual win.Isaac also can heal from Mega Satan's rock waves and mini-bosses spawned by him which spawn ignited Bombs, Troll Bombs or Megatroll Bombs. They also do plentiful damage to enemies and can open closed doors. Fetus, and Epic Fetus) combined is game breaking since as long as he gets caught by his explosions, he can heal indefinitely.
Since Isaac will have at least 10 Red Heart containers from the start, Pyromaniac and items that grant exploding shots ( Ipecac, Dr.Resetting is a perfectly good way to ensure good items. Try to get some really powerful few-item synergies.While treasure rooms are disabled in this challenge, bosses will still offer a reward upon defeating them. However, no bosses need to be defeated to progress - teleporting out of boss rooms can make the challenge much easier. If Mega Satan and Satan can be defeated, the rest of the challenge becomes significantly easier. Starting with a random selection of items, and starting on the Mega Satan boss fight makes this challenge very difficult at first.
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