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Tsukune Aono is a painfully average high school freshman who is unable to get into any private school, due to his disappointing test scores. The only school he is finally accepted into turns out to be a secret school for supernatural monsters (yōkai), who are in disguise as humans. The first student he meets is the beautiful Moka Akashiya, who becomes his friend for an unusual reason; she is a vampire, and is attracted to the sweet taste of his human blood. Tsukune quickly realizes his admission into a monster school must have been a mistake and fears for his life.
Despite Moka's vampiric nature, she is a kind girl and Tsukune quickly falls for her. He decides to stay and be near her, despite the various dangers. He must hide his human identity from the faculty and other students, while trying to keep his grades up and avoiding conflicts with the various not-so-mythological monsters lurking around campus. Tsukune soon discovers that when he removes the "rosario" around Moka's neck, she transforms into a super-vampire, stronger and more powerful than almost any other creature at the school. However, in this state, she has an entirely different personality, often cold and merciless, so the rosario is only removed in dire emergencies. Tsukune is the only person who can physically remove it to transform Moka, and only in the case of an emergency (the rosario remains physically bound to Moka, while Tsukune attempts to willfully remove it in a moment immediately preceding, and sometimes interjecting - a malignant situation). Tsukune and Moka make new friends and enemies as their stay at Yōkai Academy progresses.