- 20/20 + Brimstone - Two brimstone shots are fired, without an increase in charge time.
- 20/20 + Epic Fetus - Makes two missiles drop one after the other.
- 20/20 + The Inner Eye - 5 shots are fired with the normal decrease in fire rate instead of 3.
- 20/20 + Mom's Knife - Two knives are now thrown instead of one.
- 20/20 + Mutant Spider - 6 shots are fired with the normal decrease in fire rate.
- 20/20 + Technology - Two technology shots are fired simultaneously.
- Azazel + Monstro's Lung - Gives several additional Brimstone beams around Azazel.
- Azazel + My Reflection - Greatly increases the Brimstone laser's range and makes the laser curve as Azazel moves around the room.
- Azazel + Technology - Technology laser wraps around the Brimstone beam, dealing extra damage, but not increasing Brimstone range.
- BBF + Brimstone - BBF will fire Brimstone beams in all directions upon exploding.
- Brimstone + Dr. Fetus - Isaac continuously fires bombs while charging the Brimstone beams.
- Brimstone + Epic Fetus - Fires 10 Brimstone beams in all directions upon impact of a missile.
- Brimstone + Monstro's Lung - 3-5 additional Brimstone beams fire in random directions. One beam always fire straight forward as normal.
- Brimstone + My Reflection - Makes the beam curve when moving.
- 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 + Technology 2 - Laser fires while Brimstone is charging.
- 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.
- Death's Touch + Fire Mind - Scythes now properly explode.
- Dr. Fetus + Hot Bombs - Bombs leave behind fire that damages enemies on contact after exploding.
- Dr. Fetus + Mom's Knife - Isaac continuously fires bombs while charging the knife.
- Dr. Fetus + Monstro's Lung - Shoots 6 bombs which need to be fully charged before firing. The bombs detonate simultaneously.
- Dr. Fetus + Mysterious Liquid - Exploding bombs leave behind a large pool of green creep.
- Dr. Fetus + The Parasite - Bombs split into two bombs upon exploding.
- Dr. Fetus + Poison tears - No damage increase from poison.
- 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).
- Dr. Fetus + Spoon Bender - Bombs are purple and act as if Isaac had Bobby-Bomb.
- Dr. Fetus + Technology - Both bombs and lasers are fired.
- Dr. Fetus + Tough Love - Tears that would have fired a tooth shot instead become a bomb with the Mr. Mega, dealing more damage and shaking the screen.
- Epic Fetus + Hot Bombs - Creates a fire every time a shot lands.
- Epic Fetus + Ipecac + Sad Bombs - Tear Blast tears explode and can damage Isaac.
- Epic Fetus + Mom's Knife - Each explosion shoots 10 knives in a circle from the point of impact.
- Epic Fetus + Monstro's Lung - Adds 2 to 4 more crosshairs that orbit the main crosshair and fires a missile onto each crosshair.
- Epic Fetus + Mysterious Liquid - Exploding bombs leave behind a large pool of green creep.
- Epic Fetus + Sad Bombs - Missiles fire a burst of tears where they land.
- Epic Fetus + Spoon Bender - Cursor slides towards enemies.
- Epic Fetus + Strange Attractor - Enemies get drawn towards the crosshair.
- Epic Fetus + Spoon Bender - Cursor slides towards enemies
- 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.
- Epic Fetus + Telepathy for Dummies - Cursor slides towards enemies.
- Fire Mind + Mysterious Liquid - When the Fire Mind tear explodes, a much larger pool of creep is left behind.
- Guppy + Ipecac - Ipecac shots now spawn blue flies on hit, both direct and indirect.
- Holy Mantle + Stop Watch - Blocking damage with Holy Mantle triggers the Stop Watch effect.
- The Inner Eye + Mutant Spider - Shoots 7 tears instead of 3. No further decrease in fire rate.
- Ipecac + Mysterious Liquid - Explosions leave behind a large pool of green creep.
- The Ludovico Technique + Mom's Knife + Technology - Creates an uncontrollable laser ring centered on Isaac. The knife becomes stuck under Isaac and cannot be fired.
- 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.
- Mom's Knife + Technology - Both the knife and the laser fire normally.
- 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.
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