The story is set in the year 2011 in Neo-Kabukichō, a fictitious version of the real red-light district of Shinjuku, Tokyo. A wave of violent crime is being caused by a new contact lens drug called "Skull Eyes", enabling people to become superhumans called Kabukimono. It follows the story of the reincarnated Lion-Maru and Tiger Joe from the original Kaiketsu Lion-Maru.

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