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A nameless and highly secretive organization has created an order of superhuman warriors to protect humans from the Yoma. These warriors have come to be popularly known as Claymores, after the immense claymores they wield. Villages being attacked by Yoma hire Claymores to kill the Yoma for a large fee.

The story of Claymore follows the adventures of the Claymore warrior Clare. The plot follows her as she fights Yoma and struggles to hold on to her humanity. Starting in the 3rd volume, there is a flashback to her childhood on how she was 'adopted' by the Claymore Teresa. After Teresa rebels against the organization and is subsequently killed, Clare volunteers to become a Claymore using Teresa's flesh in order to take revenge on the Awakened who killed her. With determination and her human friend Raki by her side, Clare overcomes her low demonic power by honing the skills she inherited from Teresa, and other Claymores. As the series progresses, she becomes stronger and a better fighter, gradually earning the respect of strong allies and coming in conflict with the shadowy organization, the top Claymores who support them, and many powerful Awakened Beings.