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A huge cyclopean eye.
Isaac's usual head is replaced with that of a cyclops, and his tears become much larger. It also greatly reduces the fire rate(delay between shots = delay without Polyphemus * 2.1 + 3). Increases damage by four and then multiplies it by two. If tear does more damage than an enemy's life, the tear continues to travel with the extra remaining damage.
- The Inner Eye will retain triple shot only if Inner Eye is collected first but will also reduce the damage of each tear to a flat +5, which is the same as the effect from taking Mutant Spider with Polyphemus.
- Picking Number One after Polyphemus will not result in the usual impressive rate of fire, but rather restore your rate of fire to normal levels.
- Stacks with Chocolate Milk
- Stacks with Sacred Heart
- Stacks with Max's Head
- Stacks with Mutant Spider (keeping quad shot), decreases damage bonus of Polyphemus from (damage+4) times 2 to a flat +5.
- Dr. Fetus - Higher damage, but rate of fire is greatly reduced.
- Brimstone - Stacks, but makes charge requires longer amounts of time. However, the damage also stacks, resulting in an attack that will one hit most bosses, making even the Chest obscenely easy.
- Mom's Knife - Like above, the damage of the knife greatly increases, allowing the player to kill all enemies and bosses extremely quickly.
- Cupid's Arrow - Tears will still pierce enemies and will not lose power they kill enemies.
- Technology - Laser increases in size and damage dramatically, covering fully a fifth of the screen, though the contact area is much smaller than the laser's appearance.
- Technology 2 - Laser greatly increases in damage, killing most monsters very quickly.
- Mom's Eye - Tears will always be fired from the back of Isaac's head.
- However, Loki's Horns will not always fire from all sides when Polyphemus is collected. If Loki's Horns, Polyphemus, and Mom's Eye are all collected together, then tears will always be fired from all sides.
- Tough Love - Tears with extra damage can hit multiple enemies
- Ipecac - If an enemy is killed point blank with the tear, it will continue past the enemy in a reduced size thanks to Polyphemus, rather than exploding on contact like Ipecac normally would.
- When used with Cain, a large tear will be fired from the center (as opposed to the usual right eye).