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Claymore is a shounen fantasy/horror series set in medieval times. In the world of Claymore, monsters called "youma" run rampant. Youma prey on humans and have the ability to disguise themselves as humans, including those whom they've devoured. Silver-eyed female warriors, nicknamed "Claymores" based on the claymore swords that they wield, are dispatched by a secretive organization (simply called "the Organization") to kill youma. The true agenda of the Organization is unknown.

Claymores were once normal human girls who were unwillingly infused by the Organization with the flesh and blood of youma to give them enhanced abilities. Also a result of the infusion, Claymores gain silver eyes and pale hair. Their enhanced abilities include strength; agility; longevity; decreased need for food, water, and rest; and healing capabilities. Claymores can also release their "yoki" (youma power) in degrees to upgrade their power; however, this practice can be dangerous, since once Claymores pass a certain point, they become youma themselves (called "Awakened Beings") and can no longer revert back to their human forms. (Claymores, if they survive long enough, eventually succumb to their youma sides and awaken.) Claymores are always female, as early on in its experimentation, the Organization learned that male Claymores enjoyed releasing their yoki more than females, resulting in faster transformations into Awakened Beings. Within the Organization, Claymores are ranked by their strength, with #1 being the most powerful and #47 being the weakest.

The protagonist of Claymore is Clare, the lowest-ranked Claymore (#47) of her generation. She is the only person to have willingly become a Claymore - her desire is to find and kill a specific Awakened Being for reasons explained early on in the story. As the series progresses, however, it becomes clear that the Organization has kept secrets hidden about its motives and about the Claymores, secrets that it will go to great lengths to preserve. Additionally, the three most powerful Awakened Beings, called the "Abyssal Ones," have begun to challenge each other in a power struggle that will have irreparable consequences on the world.