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Ergo Proxy - The story begins in a futuristic domed city called Romdo, built to protect its citizens after a global ecological disaster. In this utopia, humans and androids (AutoReivs) coexist with each other peacefully under a total management system. A series of murders committed by berserk robots infected with the Cogito virus starts to jeopardize the delicate balance of the social order. Behind the scenes, the government is conducting secret experiments on a mysterious humanoid lifeform called Proxy, which is believed to hold the key to the survival of mankind.

Re-l (also spelled Real, pronounced "Rielle") Mayer is assigned to investigate some of the murders with her AutoReiv partner Iggy. She encounters a Cogito-infected AutoReiv and a fast and flexible monster. She later learns that the monster was a Proxy. The other central character, an immigrant named Vincent Law, is revealed as being the eponymous proxy, but his memories of his time in his native dome of Mosque are suppressed, or perhaps he suppresses them. After being hunted down, Vincent leaves Romdo, and Re-l tags along to discover the truth behind the Proxies and the domes.

In the domed city of Romdo (and possible in other domed cities) various sections of the 'government' are referred to as Bureaux - the Intelligence Bureau, the Health & Welfare Bureau and the Security Bureau among others. The AutoReivs are referred to as either 'companions' or 'entourage' depending on their role. Similar to films such as The Matrix, it appears that the humans in the city are somehow created and birthed by grossly swollen Autoreivs, and each assumes a purpose. This purpose, referred to as a "raison d'etre", consumes each character throughout the series. For example, Autoreiv's raisons d'etre are to serve the humans, and Daedalus' purpose is to serve and protect Real.