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For 5 years the world has teetered on the edge of disaster, resources that should have been used to control the infection and relieve suffering have instead funded a hundred border wars and civil struggles throughout Europe, Asia, Africa and the Middle-East.

The US, hardest hit by the initial outbreak, withdrew from the international scene, unable to fight to save it's own people at home, and to maintain world peace.

The infection and it's creations cared nothing for man's petty squabbles over land and resources, and the world outside the US regressed back to at best a myriad of feudal states and warlords ruled over the rubble.

In this sixth year, despite the the collapse of the Federal government, the situation in the US has stabilised,...30% of the pre-outbreak population are dead, and half of those remaining are victims of the infection, alive yet dead, while the remainder live in walled cities, remote refuges, bunkers, and in the Vaults.

Agents of the Vault-Tec Corporation, the most powerful entity to have survived the disaster, have traced the source of the infection to the area around Boston Massachusetts,...the submarine that transported the virus and the foreign infiltrators who released it on a hapless populace, lies wrecked in the Charles River, it's reactor having failed before it could make it's escape into the Atlantic.

34 sites must be sanitized at Ground Zero.

A single Vault-Tec Operator is air-lifted in to the relative safety of the north-west of the quarantined Commonwealth,...an individual uniquely suited for the task thanks to their immunity, but lacking any field experience.

Known only as Delta 06, the operator begins by looking for the Vault personnel of facility '111'....