- Ethan Thomas, a former Serial Crimes Unit investigator, is brought back into action to hunt down the killer of his former partner and uncover the disturbing secrets behind an increasingly dark and violent city.
- Eleven months after the previous game, Ethan Thomas was cleared of the charges of double murder, however his experiences have left psychological damage, he's left the Bureau's Serial Crime Unit and become an alcoholic. Bitter at Malcolm Vanhorn's manipulation of him and the people of the city becoming more psychotic, he's living in seclusion, one night in a bar, he attacks a man with metal pieces in his mouth, similar to the creatures that he fought in the last game. Thomas interacts with another homeless alcoholic to share his secret stash of booze, only to find the metal mouthed man has drank them, he sics psychotics on Thomas who fights them all off, only for the metal mouthed man to hit him with a brick and Thomas fades into a nightmare world where everything is consumed by some black ink and some masked figure is warning him not to let his resentment to Malcolm cloud his judgement.
Thomas awakens in the same alley he was attacked where Lieutenant Rosa and Agent Dorland find him, the latter is antagonistic to the washed-up Thomas. Director Farrell has ordered Thomas brought back, Malcolm has left a recording asking for help which is cut off abruptly. The call is traced to a decrepit hotel, where Thomas, alongside Dorland and Agent LeRue, fight off more violent and deformed maniacs. Thomas finds the body of an officer and follows his tracks to the room where Malcolm is, he has been murdered violently. Dorland and LeRue hurry the body to a helicopter pick-up, Thomas is lagging behind with psychotics on his tail, Dorland shoots a power transformer, halting the charging psychotics but leaves Thomas behind.
Thomas reroutes through an old doll factory to meet with Rosa, back at the station Rosa conducts an autopsy on Malcolm, his chest has been sliced open and the vocal cords removed. Thomas is given an x-ray and has another nightmare, then he's called to Farrell's office for debriefing, where Thomas' anger gets the better of him, which is interrupted by a radio message from Dorland, the city mayor, Rachael Mars has been murdered, her body found in the museum.
Her body has been mutilated and her head removed, on her body are papers bearing drawn eyes similar to the ones found near metal pieces in the previous game and the signature of Serial Killer X. Leeland Vanhorn is still alive, despite the bullet wound received in the previous game, Malcolm nursed him back to health, and evidence found shows he is Mars' killer. Curiously enough, Thomas' finds metal pieces extracted from Mars' body, they were inserted her for reasons currently unknown. Rosa meets with Ethan and reports fecal matter found on Malcolm's shoes from a species of deer found in an unspecified Black Lake region, Dorland drives Thomas to the airfield, once the latter is on the plane, Dorland informs someone that he is on board.
On the flight there the masked figure appears before Thomas and tells him that Farrell has been keeping a close eye on him for all his career, and that he may have ulterior motives for doing so. He disappears and the plane crashes. Thomas survives the crash and ventures on, he finds the bodies of armed SCU agents, Rosa knows them as Dorland's men, a savage bear has attacked them. Thomas makes it a lodge that is long abandoned yet both Vanhorns have been there, and there is considerable SCU activity, a door leading to a study has a high-grad bomb planted on it, Thomas disarms it and enters, there is a computer with a password entry, asking what makes Thomas special, his vocal cords.
On the computer is a recording from Malcolm, he mentions a group known as "Oro", Thomas' parents were members that defected and were killed, Malcolm has been fighting the Oro for most of his life as they killed his wife and child years ago, and now his nephew, Leeland, is intrigued with becoming one of them. The SCU storm the study and then LeRue saves Thomas with a snowmobile.
Rosa calls Thomas to tell that Farrell has disappeared and the police commissioner has arrived at the station, Leeland has been arrested and is held on a prison transport, LeRue takes Thomas there and helps him sneak on the bus, Leeland is heavily scarred from the bullet wound, he killed Malcolm to take his vocal cords and learn the Oro's secret, and the mayor for the same reason. The bus is attacked and Leeland escapes, Thomas chases him through a bowling alley where Thomas finds some names on a scorecard, Uncle, Mayor, Director and Magicman, all Leeland's targets, along with the severed head of Mayor Mars. Eventually Thomas enters the St Joseph's school from the previous game that Leeland has now converted into a torture chamber for the homeless. Thomas finds Farrell wounded and releases him, Leeland has been conducting experiments on the homeless, Thomas ends up in a fighting arena and defeats the test subjects, Dorland appears holding a gun to Farrell, Thomas is considered a threat to the Oro and their extensive reach, Farrell believes Thomas should be one of them, Dorland throws Farrell into the arena, where he sacrifices himself to allow Thomas to unlock the power within his vocal cords, then Leeland saves him from the SCU gunmen, calling it a "future investment".
Thomas knows the name "Magicman" and he resides at the Magic Theater. There the masked figure confronts Thomas while he's drinking, the figure is manifestation of Thomas' alcoholism, they fight and Thomas defeats him. Rosa awakens Thomas, the latter goes off to find the Magicman. Rosa provides more information of the Oro, "Oro Invictus" meaning Invincible Voice, they existed for nearly three-thousand years, they mean to manipulate the course of human evolution, it's theorized that the metal pieces within Oro members are used to channel sonic sounds to revert human minds to aggressive behavior, explaining the chaos in the city. It seems Thomas himself is capable of this sonic ability.
Thomas fights the Magicman and defeats him, the Magicman tells Thomas' that Oro fear him and he should go to a peninsula. Thomas and Rosa take a barge there, they're attacked by birds, Thomas uses his sonic ability to eliminate them all which scares Rosa off. He finds her on the lower levels and she apologizes for running off. Thomas injures his leg in a fall, yet he boards a cargo crate bound for the peninsula.
He's confronted by the masked figure again, he represents all of Thomas' demons, not just alcohol. He tells Thomas that he is the cure the Oro fear, and many have died protecting him. Thomas fights through the SCU and Oro and overloads sonic generators, eventually culminating in a fight with Dorland on a tower of junk, Thomas wins. Dorland tries to explain the Oro's intentions, to make humans hostile, combative, to be their own protectors, protectors from what is unknown. A helicopter flies down to pick Thomas up and he grabs onto the rope ladder, Dorland grabs his leg and Thomas kicks him off. On the helicopter are Rosa and LeRue, Thomas refuses a drink from the latter, and grants himself some sleep.
Three hours later the President of the U.S. is at a conference when someone slips him a note which gives him a heart attack, on the note are the words "The remedy is among us!!!"
In a final epilogue Leeland is shown undergoing surgery from the Oro to metal pieces inserted in his mouth like them.
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