(オヤシロモード in Japanese) The main story mode, featuring Keiichi as the only playable character. At the start of the story, the club has planned a Mahjong tournament and it's about time Keiichi heads out and participates. Suddenly, Keiichi receives mysterious vials of medicine from an unknown source, with a note stating the village is in danger and this is the only cure. Keiichi takes this as a prank, until he is challenged by his first opponent. Realising this isn't a joke anymore, he then runs around the village challenging his syndrome-infected friends to a game of Mahjong to save them from a potential outbreak. A mysterious entity gives Keiichi special abilities throughout his journey if the Hinamizawa Syndrome bar is raised by one level.
If the Hinamizawa Syndrome bar is not filled to L5 by the time Keiichi beats stage 7, a bad ending will occur where Takano convinces Keiichi that everything was an elaborate prank by the entire village. Keiichi, satisfied with this answer.png.png, turns around to leave. Takano then shoots him in the back of the head.
If the Hinamizawa Syndrome bar is filled to L5, a good ending occurs, where upon beating Takano, Keiichi hears a mysterious voice beckoning him to the Furude shrine. Once he arrives at the Furude shrine, an unknown yet familiar entity spawns before him, Oyashiro-sama, transporting him to a weird dimension, and challenges him to a game of Mahjong. After beating Oyashiro-sama, Keiichi remembers that the girl before him is Hanyuu, he gives her the last piece of medicine, and he snaps back into a reality shortly after, where he is walking home from school with everyone, including a human version of Hanyuu, someone who never existed in his previous fragment, but he strangely feels acquainted with. Even though it feels like one, Keiichi knows what he experienced wasn't a dream and appreciates everything he learned from the Mahjong competition.
Cheats in this game mode can only be acquired by picking out cards on screen that appear every time the player wins a match. By levelling up the Hinamizawa Syndrome, mysterious entity multiplies or gives the player a random cheat(s). The Ippatsu Riichi cheat is always given after the player continues to play as Keiichi gives one of his game-over speeches.