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inFAMOUS is set in Empire City, a fictional metropolis based on New York City, consisting of the Neon District, where most of Empire City's businesses are concentrated, the Warren, a slum dependent on international shipping activity, and the Historic District, the location of the city government. Each district has an elevated train system and a separate power grid. The premise of the game is built around the partial destruction of the Historic District by a mysterious explosion, followed by a viral epidemic that forces federal authorities to seal the only bridge leading to the mainland. A rise in violent crime overwhelms the police, resulting in societal collapse.

The protagonist is Cole MacGrath (Jason Cottle), a courier who is accused of triggering the explosion, which leaves him with the ability to absorb and project electricity. His closest friend, Zeke Jedediah Dunbar (Caleb Moody), allows Cole to hide on his rooftop, despite his envy of the former's powers. Trish Dailey (October Moore), Cole's girlfriend, abandons him out of anger over the death of her sister Amy, while most of Empire City's residents view him as a terrorist. While attempting to escape the city with Zeke, Cole is contacted by FBI agent Moya Jones (Kimberli Colbourne), who offers to clear his name if he helps her find her husband, fellow agent John White (Phil LaMarr). White vanished while investigating a group known as the First Sons, who are believed to be responsible for orchestrating the explosion.

While working to restore order in the Neon District, Cole encounters Sasha (Jessica Straus), a former member of the First Sons, who like Cole is a "Conduit", an individual given powers by the First Sons. Using her ability to control the minds of others via a tar-like substance, she has formed a gang known as the Reapers. Meanwhile, the Warren has been overrun by the Dust Men, an army of homeless militants led by Alden Tate (also Jason Cottle), the original leader of the First Sons, who possesses telekinesis. Kessler (Sam A. Mowry), the true antagonist of the game, is a shadowy figure who controls the First Sons and who takes an obsessive interest in Cole and his powers.

While the basic story of InFamous remains unchanged whether the player opts for the "Good" or "Evil" karma path, there are some story elements that change depending on Cole's choices.

While making a delivery in the Historic District, Cole is instructed to open the package. In doing so, he activates a device known as the Ray Sphere, leveling six city blocks and nearly killing him. Rescued by Zeke and Trish, he teaches himself to control his emerging powers. After using them in public to fight off a Reaper attack, the locals turn against Cole after he is accused of triggering the explosion, forcing him into hiding. He and Zeke engineer an assault on the sealed bridge, only to be ambushed by government forces. Separated from his friend, Cole meets Moya, who persuades him to return and find John. With her help, Cole restores the district's power supply, earning the attention of Sasha, who lures him into her underground lair. Cole defeats her, but she is abducted by the Sons before he can make her talk. Trapped in the Warren, Cole assists what remains of the police in battling the Dust Men. Alden is arrested and imprisoned, but Zeke's incompetence in guarding him allows the Dust Men to free him and massacre most of the officers. With Alden planning to reactivate the Sphere, the two patch things up and confront him, with Zeke ending up in possession of the Sphere. Giving in to his temptations, Zeke deserts Cole and takes the Sphere to Kessler.

With Alden on a murderous rampage towards the Historic District, Cole defeats him once and for all in a bridge battle. Before jumping in the water, Alden reveals that Kessler exiled him from the First Sons. White, who turns out to be an NSA agent with no connection to Moya, reaches out to Cole and explains that the Ray Sphere is designed to consume bio-energy from thousands of lives and transfer it to a single user, making them a Conduit. During their search for the Sphere, Kessler publicly challenges Cole to stop a series of bombings across the district, ending with him being forced to choose between saving Trish or her colleagues. Regardless of which choice he makes, Cole fails to keep Trish from dying. Determined to punish Kessler, Cole tracks the Sphere to a remote pier, where he must decide whether to destroy it or use it to become even more powerful. Regardless, the Sphere releases the last of its energy, killing John before disappearing into a vortex.