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Known for its Space Western theme, Trigun is about a man named "Vash the Stampede" and the two Bernardelli Insurance Society employees who follow him around in order to minimize the damages inevitably caused by his appearance. Most of the damage attributed to Vash is actually caused by bounty hunters in pursuit of the "60,000,000,000$$" (sixty billion "double dollars") bounty on Vash's head for the destruction of the city of July.

Set on the fictional year of 2010, the world has been split into 3 superpowers: The Holy Britannian Empire (the Americas; also called Britannia), the Chinese Federation (Asia), and the European Union (Europe and Africa; previously known as the Euro-Universe. Also known as Europa United in Akito the Exiled).