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Isaac's Heart is a secret unlockable passive item.
- Isaac's body becomes immune to all damage.
- A heart familiar appears and closely follows Isaac. If the heart is hurt, Isaac is hurt.
- Most enemies now target the heart instead of Isaac. Eyes and other similar enemies, however, will still target Isaac.
- Items that activate on contact with enemies retain their ability, allowing Isaac to use them without suffering collision damage.
- Isaac can use Blood Donation Machines and Demon Beggars without taking damage.
- During The Guardian challenge, Demon Beggars and Blood Donation Machines deal damage to Isaac.
- Curse Rooms don't deal damage when entered. When used properly, it can allow The Lost to enter and exit Curse Rooms without risk of death.
- Even if Isaac himself can't fly, the heart will hover over ground hazards, making Isaac immune to all damaging creep and spikes. However, the spikes in a Sacrifice Room can still damage it.
- Picking up a non-orbital familiar will cause either Isaac's Heart or the other familiar to be layered over the other's sprite. This is due to the heart not taking up the spot that the other familiar follows in.
- Enemy Brimstone shots (such as from The Bloat) will not deal any damage to the heart.
- Brimstone shots will damage the heart.
- Additional players gain the immunity effect without spawning additional hearts.
- Enemy beams of light (similar to Crack the Sky) will not deal any damage to the heart.
- Aries - Isaac can cause contact damage without taking damage.
- Blood Rights - Isaac can use Blood Rights infinitely without taking damage.
- Breath of Life - Isaac can be infinitely invulnerable, as invincibility carries out to the heart without hurting the player. Note that the item needs to be activated for longer than one second for the invulnerability to kick in, however.
- Blank Card + XIV - Temperance - Isaac can reuse the Temperance card to get effectively infinite money.
- Dry Baby - If Isaac's Heart is layered over Dry Baby, Dry Baby will block incoming shots and the heart will not be damaged by projectiles. Enemies touching the heart can still do damage.
- Duct Tape: Isaac's Heart will stay in place relative to Isaac.
- E Coli - Isaac can turn enemies into poop without taking damage.
- Extension Cord: Isaac's Heart and Isaac will occasionally be connected via electricity.
- Gnawed Leaf - Invincibility carries over to the heart.
- Holy Mantle - The shield effect carries over to the heart.
- IV Bag - Isaac can use the bag without taking damage, granting infinite money.
- Kamikaze! - As long as the heart is away from the blast radius, no damage is taken. Character must be at high enough speed for this.
- Midas' Touch - Isaac can turn enemies into coins on contact without taking damage.
- Razor Blade - Isaac cannot take damage from the Razor Blade, allowing for infinite uses of the item.
- The Nail - Demon Isaac can cause contact damage without taking damage.
- The Virus - Isaac can poison enemies on contact without taking damage.
- Box of Friends - Box of Friends does not duplicate the heart.
- BFFS! - BFFS! will make the heart bigger, making it easier to get hit.
- Duct Tape: Familiar will stay in place relative to Isaac.
- King Baby - The Heart will follow King Baby. This makes it much harder to avoid damage, but also makes other synergies like Kamikaze! much easier to use.
- Sharp Plug - Sharp Plug can no longer be used.
- The Soul - Isaac's body repels projectiles, but Isaac's Heart doesn't.
- Isaac's Heart while it's following Isaac fittingly shares the same sprite as Child's Heart.
- The nature of the item is similar to that of a Mask + Heart enemy.
- This item is used in Challenge #30 (The Guardian).
PC TPWZ 7CVR (Treasure Room below of spawn)
PC PCJZ 03TG (Adjacent Treasure Room)
PS4 W1TD 0BJN (Treasure room south of spawn)