These curses cannot be stopped through the usual methods of removing curses, such as the Rune of Dagaz, Black Candle or Genesis.
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.
Hearts of any kind – red, soul, black, eternal, bone, golden, blended and rotten hearts – do not appear on this run.
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 V - 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.
This forces the player to progress through Sheol and the Dark Room 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.
Some players report no victory trophy spawning after defeating Delirium, under unknown conditions. It may not be safe to attempt this route.
Defeating Delirium by traveling to The Void after defeating Hush spawns the trophy. Collecting it will still complete the challenge as normal.
Strategies[ | ]
Attempt to find valuable items from the two items rooms that appear in the Basement.
Note that Isaac does not start with The D6, making rerolling items at the start of a run impossible without the use of a rune such as Rune of Perthro or Soul of Eden.
Aside from trying to find powerful items such as Polyphemus,Mom's Knife, or Tech X, trying to find items that grant health regeneration is invaluable.
Also attempt to look for synergies such as Blank Card and XIX - The Sun or Placebo and a Full Health or Bad Trip pill. These synergies can easily win the Ultra Hard challenge provided the player has means to defeat difficult bosses such as The Lamb and Mega Satan.
The D10 can be surprisingly helpful; most of the time, it will reroll enemies into non-champion forms, and as the D10 can never reroll enemies into portals, it makes managing rooms with portals much easier.
The D10 rerolls champion enemies into new champion enemies. Additionally, portals no longer spawn outside of The Void.
The Glowing Hourglass will allow the player to retry difficult rooms, avoid detrimental items, and peek at pills without the risk of harmful effects.
Trinkets that drops hearts as pickups such as Bloody Penny or Monkey Paw are useless in this challenge. However, those that directly heal such as Isaac's Fork or Stem Cell will still function.
PHD is very valuable, as it reveals all pills, replaces detrimental pill effects with positive ones, and heals two red hearts upon pickup.
Hematemesis is a major problem in this challenge as it drains all your red hearts and does not give them back.
Items that reroll the player such as the D4 and the D100 can be used to amass health very quickly, as hearts generated from items are not removed if the items that granted them are rerolled.
Items lost from the D4 and the D100 now remove associated hearts.
The Clicker can potentially transform Isaac into Keeper, allowing him to heal with coins. That said, using it will remove your most recently collected item, so it shouldn't be used if it would remove a powerful item or Key Piece 2.
Clicker can no longer spawn in challenges.
Look for Library and Bedrooms. Both of these rooms contain resources that can replenish the player's health.
Rainbow Poops can be destroyed to fully heal the player.
Bombing Tinted Rocks is much less beneficial for the player, as soul hearts will not drop from them.
Tinted Rocks can still contain The Small Rock, however, so if the player has a surplus of bombs or another way to destroy rocks, there is no reason to not destroy them.
Deals found in Devil Rooms are generally not worth taking. It may be preferable to pursue Angel Rooms instead, as the player already has both key pieces, which greatly increases their chances of spawning. Due to no Soul hearts or Black hearts being able to spawn naturally, taking damage and lowering the chance for a Devil / Angel room is very common. Make sure to find items that give these hearts such as Book of Revelations or Satanic Bible.
One-heart deals are almost never beneficial — many one-heart deals do not pay for themselves, whether that be in health or other effects. Avoid taking one-heart deals unless you are confident that they are worth their cost.
Two-heart deals are very powerful, such as The Pact and Brimstone. Be wary that Abaddon can remove the player's red hearts, making items such as Pyromaniac, Yum Heart and Placenta useless until the player regains red hearts.
Judas' Tongue and Your Soul will hide two-heart deals due to Curse of the Blind. Therefore, if you plan to use them, you should make sure to drop the trinket once you enter the devil room to be sure if you're actually getting a 2 heart deal.
Satanic Bible now changes the Boss Room item into a Devil Deal, which depending on the item cost (as 2 heart deals generally provide better items), is not recommended
If Red Chests spawn in the Devil Room, be wary of picking up any items that they may contain. The Red Chest item pool contains powerful items such as Dead Cat but also contains potentially run-ruining items such as Cursed Eye and Curse of the Tower.
Curse Rooms very rarely contain a worthwhile item, and as Curse of the Blind is in permanent effect, it is impossible to tell if an item in a Curse Room contains a good item, such as Dead Cat, or a bad item, such as Curse of the Tower.
Sacrifice Rooms do allow the player to potentially obtain a powerful Angel Room item; however, spending at least three full hearts for a chance at getting an item is almost always not worth it, especially as hearts do not naturally drop. Additionally, there is no reason to fight the angels, as the player already has both key pieces, and there is no reason to teleport early to the Dark Room and skip multiple Treasure Rooms, as the player is forced to take The Negative anyways.
The Colorful Baby, which can be utilized in co-op mode, makes the Ultra Hard challenge trivial, as its healing effect can be used infinitely.
Due to the permanent Curse of the Blind and the inability for hearts to drop, Binge Eater is an extremely powerful item as long as you can time the item swapping properly. This removes the worry of most harmful items while supplying a lot more healing and stats, and even allowing Devil Deals to be utilized to their fullest extent. The only drawback is the fact it is from the Secret Room pool, therefore making it very hard to come across. If you have the patience to farm Secret Rooms for this item, it can essentially guarantee a win.
Shard of Glass is a very dangerous item in this challenge, as once damaged, there are no ways to stop the health draining effect unless you find an HP up, as heart pickups of any kind cannot spawn in Ultra Hard.
Despite being the "Ultra Hard" challenge, this challenge is actually played in Normal Mode. Although it is not as noticeable in Afterbirth, in Repentance, it is far easier to notice due to the lowered shot speed of many enemies.
Mega Satan battle and has to beat Mega Satan through the Dark Room.
Curse of the Labyrinth, 
Even though the option to proceed upward through the 
The Lamb Unlocks 
??? (Boss) Unlocks 
Mega Satan Unlocks 
Challenges 
The Binding of Isaac: Rebirth
