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Blood+ - Under the care of her adoptive family, Saya Otonashi has been living the life of an anemic and amnesiac, but otherwise ordinary schoolgirl. Saya’s happy life is shattered when she is attacked by a chiropteran, learning that she is the only one who can defeat them.

Armed with her katana, Saya embarks on a journey with her family, allies, and her chevalier, Haji, to rid the world of chiropteran and rediscover her identity. The course of the journey reveals the background history of the chiropterans and Saya's very deep past, which extends into the mid-19th century.

The series is initially set in present day Okinawa City (Koza), on Okinawa Island, near the US Kadena Air Base. In the course of the series, Saya visits locations across the world, fighting enemy chiropteran and searching for her origins.