Ultra Hard

Ultra Hard is Challenge #34. Isaac begins with both halves of the key for the Mega Satan battle, and has to beat Mega Satan through the Dark Room.

Difficulty

This challenge, like the name suggests, is extremely difficult:

All enemies with champion forms, including bosses, will be champions.
- Champions will not drop any collectibles.
The player suffers from the following curses each floor: Curse of the Labyrinth, Curse of the Lost, Curse of the Maze and Curse of the Blind.
- These curses cannot be stopped through the usual methods of removing curses, such as the Dagaz rune.
- In addition to the four curses, the player may additionally suffer from either Curse of the Unknown or Curse of Darkness, which can be removed through usual means.
There are absolutely no hearts to be found in this run - red, soul, black, or eternal hearts.
- Hearts can still be obtained through passive items that grant them upon collection, such as Super Bandage or Latch Key.
- Items and cards that normally drop hearts such as The Hierophant tarot card will not drop any hearts. Using an Ace of Hearts card will consume all pickups in the room, and not drop any hearts.
- However, items that add hearts directly to the player's count (such as Balls of Steel or the Satanic Bible) will work.
Every boss fight that can be, will be double trouble.
- Since the Basement can't have double trouble bosses, these don't start until the Caves.
Only The Negative drops after killing Mom.
- This forces the player to progress through Sheol and the Dark Room in order to fight Mega Satan.
  - Even though the option to proceed upward through the Cathedral is presented, the run will end after defeating Isaac and touching the chest will not give the player credit for completing the challenge.
    - The player can also beat the challenge by defeating Delirium.
- Because the player cannot progress through The Chest, they are unable to take advantage of the 4 items at the start of the Chest floor.
If the player manages to defeat Hush, the entrances to the Cathedral, Sheol, and The Void appear.

Strategy

Attempt to find a good starting combination from the item rooms in the Basement XL. Aside from getting something powerful like Mom's Knife, getting something that grants HP regeneration is strongly recommended too, such as Pyromaniac, Leech, Charm of the Vampire, or Placenta (can be found in the Basement or Caves from bosses).
The D10 can also be surprisingly helpful, as, most of the time, it will reroll enemies into non-champions, and never spawn new portals.
While the Challenge can likely be completed with accepting Devil Deals, it would be a better idea to attempt to choose Angel Rooms instead, since items that can make or break the player's victory could be found without sacrificing valuable heart containers. However, it should be noted that the Satanic Bible and the Nail are extremely good items for the run, and they may happen to be the two heart deal in the Devil Room. Libraries also contain books that can give health, such as the Book of Revelations and the Satanic Bible.
Eating unknown pills can be very dangerous, because Hematemesis reduces you to one heart without dropping any hearts. Identifying a Full Health, Balls of Steel or a Bad Trip pill early can be very beneficial, however. Thus, it is recommended to take PHD whenever you get the chance. PHD itself can also heal you for 2 Hearts.
Curse Rooms, generally, should be avoided because they cannot contain soul hearts.
- Curse Rooms can generally be entered on the first floor, where the challenge can be restarted if it does not contain a beneficial item.
Be aware that Clicker can remove the Key Piece 1 and Key Piece 2 passive items given at the start of the run.
When playing co-op, having a Colorful Baby on start makes the run extremely easy, as the healing effect has infinite uses.
Bedrooms will still heal all the player's hearts, but can only be used once.
Rainbow Poop will still heal Isaac to full health.
Obtaining Blank Card and The Sun, or Placebo and Full Health/Bad Trip and can make this challenge a lot easier, as it allows you to restore your health every 4 rooms (or for Bad Trip's case, when you are at one red Heart or less). If you enter the Mega Satan fight with full health and any of these combinations, you basically have at least 3 full health bars (4 if you have Starter Deck or Little Baggy) for the final boss fight.
The D4 and the D100 can be very helpful, since heart containers from health up items will not be removed when used when rerolling collectibles. This allows the player to quickly amass heart containers.