- 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 + Technology - Technology laser wraps around the Brimstone beam, dealing extra damage, but not increasing Brimstone range.
- 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.
- BBF + Brimstone - BBF will fire brimstone beams in all directions upon exploding.
- Brimstone + Dr. Fetus - Isaac continuously fires bombs while charging the blood laser. Overrides Azazel's blood laser.
- Brimstone + Epic Fetus - Fires lasers in all directions upon impact of a missile.
- Brimstone + Monstro's Lung - Several additional lasers fire in random directions. One beam always fire straight forward as normal.
- Brimstone + My Reflection - Makes the beam curve when moving.
- Brimstone + Proptosis - Doubles damage but it rapidly decreases with distance, down to 0.1 from about 6 tiles away.
- Brimstone + Technology - The Technology laser coils around the Brimstone beam, granting a 1.5x damage multiplier.
- 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 + 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 + Spoon Bender - Cursor slides towards enemies.
- Epic Fetus + Telepathy For Dummies - Cursor slides towards enemies.
- The Inner Eye + Mutant Spider - Shoots 7 tears instead of 3. No further decrease in fire rate.
- Mom's Knife + Technology - Both fire normally.
- My Reflection + Technology - Makes the beam curve when moving. Has the same effect on Azazel's mini-brimstone and doubles the range.
- Mysterious Liquid + Technology - The laser spawns pools of liquid always when it hits obstacles and occasionally on enemies.
- Rubber Cement + Technology - Lasers bounce off of walls.
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