Box of Friends is an unlockable activated item added in Afterbirth.
- Upon use, it adds one copy of each of Isaac's familiars for the duration of the current room.
- If Isaac has no familiars, a
Demon Baby
Follows Isaac and automatically fires at enemies in its reach. will spawn for the duration of the current room.
- Lilith starts with this item by default, even if it hasn't been unlocked yet.
- If Isaac has more than one copy of the same familiar, it will still only add one copy.
- Blue Flies, Blue Spiders, and orbitals (
Halo of Flies
Spawns two pretty fly familiars that block enemy shots and deal contact damage to enemies., 
Leprosy
Upon taking damage, grants a body part as an orbital, which blocks enemy shots and deals 7 damage per tick to enemies it comes in contact with. The orbitals will be destroyed if they take enough damage from enemies or enemy shots., etc) are not copied.
- Many familiars can be spawned in Greed mode and Boss Rush, as completing waves charges the item.
1up!
Gives an extra life. Upon death, you will respawn in the previous room with full health and lose the 1up!. /
Dead Cat
Sets the amount of red heart containers to 1, but gives Isaac 9 extra lives. After dying, Isaac is teleported to the last safe room. New heart containers can be obtained after picking up this item, but after each death, the number of heart containers is set to 1 again.: Familiars are multiplied but do not give Isaac additional lives.
Abel
A familiar that mirrors the player's movements and shoots in the opposite direction. /
Dead Bird
Spawns a flying familiar for the current room that chases enemies whenever Isaac takes damage. /
Eve's Bird Foot
5% chance to spawn a Dead Bird familiar for the current room each time an enemy dies. /
Isaac's Heart
Isaac himself is now immune to all damage, and a heart familiar appears and follows Isaac. If the heart is hurt, Isaac is hurt. /
Isaac's Head
Gives the player Isaac's severed head as a tear-firing familiar. Fires piercing tears. /
???'s Soul
Spawns a familiar that floats slowly around the room on a pattern similar to The Peeper and fires spectral and homing tears.: These familiars are not copied.
Milk!
A glass of milk follows Isaac and spills on the floor upon taking damage. After the milk spills, Isaac's tear delay is decreased by 2 for the rest of the room.: The familiar itself doesn't appear, but instead it decreases tear delay by 2 (effective tears up) when used, without needing to take damage.
Best Bud
When hit, summons a white attack fly similar to Distant Admiration for the current room.: If used before taking damage, the white fly will circle around Isaac. However, multiple white flies cannot be spawned, so using Box of Friends after taking damage or using it multiple times in a room has no effect.
Bumbo
Spawns a beggar familiar which floats around the room and picks up any nearby coins, leveling up after collecting several coins. At level 2, Bumbo gains a body. At level 3, it begins to fire tears. At level 4, Bumbo chases enemies slowly, dealing contact damage.: Will spawn a level 1 Bumbo regardless of the original Bumbo's current level.
My Shadow
Each time Isaac takes damage, inflicts fear on all enemies in the room and spawns a black friendly Charger that will attack enemies. The Charger will be killed if it is damaged too much.: No effect.
- Pickup generation familiars: The copied familiars will drop pickups independently.
Guillotine
Isaac's head is removed from his body and floats around him. Increases Damage by 1 and grants -1 Tear Delay.: Duplicates the Head circling around Isaac's body. Only one head will shoot tears.
Key Piece 1
Combined with Key Piece 2, unlocks the golden gate in the starting room of The Chest and Dark Room to fight Mega Satan. /
Key Piece 2
Combined with Key Piece 1, unlocks the golden gate in the starting room of The Chest and Dark Room to fight Mega Satan.: Key pieces are multiplied, but do not complete the other half.
Bob's Brain
Spawns a familiar that charges forward when shooting tears and explodes upon contact with an enemy, damaging and poisoning them. The familiar respawns after a few seconds.: When used upon entering a room, Box of Friends eliminates the item delay, which allows Isaac to launch Bob's Brain immediately.
Car Battery
Causes Isaac's activated item to activate twice on each use.: Adds two copies of each familiar.
Cube of Meat
Orbiting familiar that blocks enemy shots and deals damage to enemies. If collected while already having one, makes the familiar evolve. Only drops from Horsemen. Similar to Ball of Bandages. /
Ball of Bandages
Orbiting familiar that deals damage to enemies. If collected while already having one, makes the familiar evolve. Only drops from Horsemen. Similar to Cube of Meat.: Upgrades the cube/ball for the current room. This can be used to easily unlock the Super Meat Boy and Bandage Girl achievements.
Daddy Longlegs
Daddy Long Legs' shadow follows Isaac and stomps on enemies.: Familiar will be copied.
Incubus
A demonic familiar that follows Isaac and shoots tears identical to Isaac's in terms of damage, range, fire rate, and effects.: Creates additional Incubus familiars, which share the same tear modifiers as the player.
Multidimensional Baby
Spawns a familiar that will follow Isaac's movements on a 2.5 second delay. Tears that pass through the baby will be doubled and increase in speed.: Each copy of Multidimensional Baby follows the previous copy with a 2.5 second delay.
Smart Fly
After Isaac takes damage, this fly will deal continuous touch damage to whatever enemy caused the damage until it is dead. The fly will then systematically attack 1 enemy at a time until the room is cleared.: Very useful on Greed mode, as each usage will add an attacking fly, killing enemies and bosses very quickly.
- The Box of Friends seems to resemble the Lament Configuration of the Lemarchand's box from Clive Barker's Hellraiser.
- Might be a very obscure reference to a Yu-Gi-Oh! card with the same name.
- This item used to have a recharge time of 2, until an update on November 4, 2015.
- When playing in Korean, this item still has a recharge time of 2.
- In the game files this item's sprite is called "Pandora's Box" by a mistake.
Switch
WL8W DS4S (First Golden Treasure Room)