Once transformed, Isaac will gain flight and an enhanced version of The Mulligan, which always spawns Attack Flies when he or his familiars' tears strike an enemy.
Having picked the items up at some point is the only thing that matters, so even though Guppy's Head and Paw are both activated items, Isaac will still transform even if he picked up one of them earlier and left it behind, or rerolled it with The Dice.
Therefore, the latter can be a method to acquire another Guppy item. For instance, if Isaac has The Dice and found Guppy's Paw in the Devil Room, he can pick it up, then switch back to the Dice to reroll it for another Devil Room item, potentially being another Guppy item.
The Left Hand Trinket can increase the likelihood of becoming Guppy, since it turns all future Chests into Red Chests, which can contain Guppy items. This has good synergy with Guppy's Tail as well, since it increases the number of Chests appearing, which become Red Chests with the Left Hand.
If Isaac gets a duplicate of Guppy's Tail or Guppy's Head, it will be counted toward becoming Guppy a second time.
Interactions
The Parasite completely eliminates the ability to spawn Attack Flies when Isaac's tears strike an enemy. Tears from Familiars will still produce Attack Flies.
Chocolate Milk makes uncharged Attack Flies deal no damage. If charged, they will deal the bonus damage associated with charging shots. Uncharged Attack Flies still instant kill Black Fly, Attack Fly, Pooter and Fat Fly.
Transcendence No effect, You are already flying and your head will not be severed from the body.
Found in the Devil Room, Curse Room, Red Chests, and as a drop from Super Pride. Isaac's heart containers are set to 1 and he is given 9 lives, as well as a dead cat head Familiar. Health upgrades can be taken as normal, but upon dying, his heart containers will be reset to 1 again.
Found in the Devil Room, Curse Room or Red Chests. Upon activation, turns one Heart Container into 3 Soul Hearts. This item's primary function has no effect for ???.
Loosely follows behind Isaac. Can be swung like a flail by Isaac rapidly spinning in a circle.
Deals damage when it collides with enemies. If an enemy is killed by the ball, it increases in size up to a maximum limit. The larger the ball becomes the easier it is to swing, the larger its collision circle becomes and the higher its damage becomes. Size is reduced at the start of each floor.
Collecting Guppy's Hairball does not count towards becoming Guppy in the vanilla game, but does as of the Eternal Edition update.
Related Achievements
"Guppy's Hairball" - Collect three Guppy-related items in a single playthrough.
Trivia
Since the game's Prologue doesn't tell anything about Guppy, this cat is probably long dead by the time Isaac explores the world under the trapdoor, since pieces of him can be found throughout the adventure and eventually Isaac can also find Dead Cat which represents Guppy himself. Given that in Isaac's death note the boy leaves everything to Guppy, it's also possible that Guppy is Isaac's imaginary friend .
Guppy is actually a reference to Edmund McMillen's own pet cat called Guppy. Guppy passed away on August 19, 2014 at the age of 12.
Guppy is intended to appear in Edmund's upcoming game Mew-Genics.
Bugs
If the third Guppy item Isaac picks up is an activated item, the game may bug, so he may have to switch out the final active item before becoming Guppy.
"Guppy's Hairball" - Collect three Guppy-related items in a single playthrough.
