The story of Melty Blood follows one year after Satsuki Yumizuka's non-existent route. Shiki Tohno hears of a new series of murders in Misaki similar to the one's that took place during Tsukihime. Whilst searching for the murderer he meets Sion Eltnam Atlasia who initiates a fight with him, attempting to capture him. After the fight she reveals that her reason for trying to capture him is to get in contact with the "True Ancestor" (referring to Arcueid) so that she may acquire information on the "cure for vampirism". Shiki then decides to help her with this task.
The story moves through a series of fights. Depending on the outcome of the fight the story will branch in one of two ways. Ultimately this corresponds to the ending of the game.