In Mahjong Vanilla Syndrome, the player takes the role of a young man who finds a mysteriously-looking little house, opens the door - and falls through a portal into another dimension! There, he is greeted by a cute bunny-eared girl named Vanilla (perhaps it should have been Bunnyla, but we'll never know), who says she is the guardian of the portal, and if he wants to return home, he'll have to defeat her and the other guardians in the game of mahjong!

The game has two modes: story mode, which puts the player against Vanilla and advances the story after mahjong rounds; and battle mode, which allows the player to choose between three cute female opponents, and also change some of the game's rules.