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The type of randomized tear changes every 2–3 seconds. The item appears to select two tear effects at once, perhaps staggering the times at which each of those effects changes.
If a run is quit, and then continued, 3 Dollar Bill will keep tear effects for the current room.
Dies after taking too much damage and then respawns after a long time. Exiting and continuing the run will cause it to reappear right away.
Dies instantly by enemies' beam-type attacks, such as Uriel's and Gabriel's beam. This also includes enemies' Technology lasers such as Eye and Camillo Jr..
Reappears instantly each time a familiar or orbital item is picked up.
Brimstone + Mysterious Liquid - When Brimstone hits enemies or walls it leaves creep based on how long it hits.
Brimstone + Proptosis - Doubles damage but it rapidly decreases with distance, down to 0.1 from about 6 tiles away.
Brimstone + Rubber Cement - Brimstone beam bounces off walls, creating a second beam that does half damage. Azazel's Brimstone will continue to full length after bouncing but will deal half of the damage.
Brimstone + Sad Bombs - Bombs explode into Brimstone beams in all directions.
Brimstone + Tech.5 - Tech.5 fires at player's tear rate while Brimstone laser is charging.
Brimstone + Technology - The Technology laser coils around the Brimstone beam, granting a 1.5x damage multiplier.
Brimstone + Tough Love - Occasionally fires Brimstone beam with damage multiplier of Tough Love.
Broken Watch + Stop Watch - Both the slow effect and the rarer speed up can trigger at the start of a room. However, getting hit in a sped-up room will trigger Stop Watch's slow down.
Cricket's Body + Dr. Fetus - Bombs split outwards into 4 tiny bombs that are not affected by Isaac's bomb modifiers, which detonate almost immediately.
Dr. Fetus + Polyphemus - Bombs become Mr. Mega bombs. After they explode, they leave behind a regular-sized bomb.
Dr. Fetus + Sad Bombs - Fires tears as normally placed Sad Bombs would. If this synergy is combined with Ipecac, the tears from the bomb become explosive, which Isaac is not immune to. Tears fired from previous Dr. Fetus bombs can collide with other Dr. Fetus bombs (can be negated with spectral tears).
Epic Fetus + Technology - Explosion shoots Technology lasers in all directions. When firing/moving the cursor, Isaaac still shoot his Technology laser.
Epic Fetus + Technology 2 - Both the Technology 2 laser, and the Epic Fetus missiles will be active.
The Ludovico Technique + Monstro's Lung - Tear becomes a cluster of variably sized tears spread over a small area. The tears move at the same speed when controlled but constantly move around each other.
The Ludovico Technique + Mysterious Liquid - Pools the size of the tear constantly form on the ground dealing large amounts of damage to any non-flying enemy inside the tear.
A Lump of Coal + Brimstone - Beam will gradually increase in size and damage the farther it travels, on a multiplier that is roughly +20% per tile of distance.
A Lump of Coal + Technology - Damage increases the further away the enemy is, on a multiplier that is roughly +20% per tile of distance.
A Lump of Coal + Technology + Tiny Planet - The extra distance covered by the laser more than doubles damage right in front of Isaac, and it increases as normal further away.
A Lump of Coal + Technology 2 - Damage increases the further away the enemy is, on a multiplier that is roughly +20% per tile of distance.
Mom's Knife + Monstro's Lung - Fires a cluster of 3-5 knives at maximum charge, each dealing 2x damage.
My Reflection + Technology - Makes the beam curve when moving. Has the same effect on Azazel's mini-brimstone and doubles the range.
My Reflection + Technology 2 - Laser is bent as Isaac moves, then gradually becomes straight as he stands still.
Mysterious Liquid + Technology - The laser spawns pools of liquid always when it hits obstacles and occasionally on enemies.
Proptosis + Technology - The beam decreases in damage and width the farther it travels. Tears become virtually powerless across large rooms like the Boss Rush and the Hush fight.
Proptosis + Technology 2 - The beam decreases in damage and width the farther it travels. Tears become virtually powerless across large rooms like the Boss Rush and the Hush fight.
Pisces + Technology 2 - Laser can knock back enemies well due to its high fire rate.
Rubber Cement + Technology - Laser bounces off of walls, creating a second beam that does half damage.
Rubber Cement + Technology 2 - Laser bounces off of walls, creating a second beam that does half damage.
Troll Bombs are now given a random amount of time before exploding. Before that, they always exploded at a fixed time. This means that if two Troll Bombs spawn at the exact time right next to each other, there's a high chance one Troll Bomb will blow up before the other, sending that Troll Bomb sliding outwards a bit before exploding.
Donating to a Beggar until it pays out with an item on the current floor applies a 10% bonus instead of 25%.
Donating to a Devil Beggar until it pays out with an item on the current floor applies a 10% bonus instead of 25%.
If this coin flip succeeds, a Devil Room will be generated regardless of the above coin flips.
"You feel blessed!" fortune in the Sacrifice Room of the current floor applies a bonus:
If the "You feel blessed!" fortune appeared on the 3rd sacrifice, the chance will be 15%.
If the "You feel blessed!" fortune appeared on the 5th sacrifice, the chance will be 50%.
If both "You feel blessed!" fortunes appeared, the chance will be 65%.
Angel Rooms that spawn after Isaac defeats Mom's Heart or It Lives will be normal Angel Rooms with items or pickups.
A Troll Bomb can sometimes appear behind the Angel Statue, blowing it up. If the Angel fights have been unlocked, this will begin the boss fight if the player is not careful or quick enough to move the bomb.
There is a chance that there will only be 2 items to choose from. Additionally, items may be trapped behind rocks or spikes. Items may appear in the corners of the room instead of the center.
All 15 waves are randomized. Each wave spawns two random bosses from the list. Each boss can only appear once per Boss Rush.
Does not increase the chance of a Devil/Angel room after defeating a boss, only the chance of getting an Angel Room over a Devil Room.
Can cause an Angel Room to spawn even if you already took a deal with the devil.
Less of a modifier than the "You feel blessed!" effect below.
4th
50%
Nothing
50%
1 random chest (The type of chest is governed by the same mechanic as room drops. Thus, brown chests are more likely to spawn than any other kind of chest.)
5th
33%
3 Pennies (These coins do not have a chance to spawn as a nickel or a dime.)
67%
You feel blessed!" (Same conditions as 3rd sacrifice but a stronger modifier.)
6th
33%
Teleport to the Devil/Angel Room. (If the floor's Devil/Angel Room has not been entered yet, an Angel Room is guaranteed to spawn — even if you already took a Devil Deal.)
67%
1 random chest (The type of chest is governed by the same mechanic as room drops. Thus, brown chests are more likely to spawn than any other kind of chest.)
The floor icons on the stage transition sprites are updated; instead of being large rectangles with the unknown ones being grey, the sprites feature a much thinner and more detailed border with the unknown floors being represented by a closed trap door.