Angela Vidal (Jennifer Carpenter) and her cameraman Scott Percival (Steve Harris), a late night television host and crew duo, set out to film a report on the night shift of a Los Angeles fire station. Angela and Scott are introduced to firefighters Fletcher (Johnathon Schaech) and Jake (Jay Hernandez).
A medical emergency at an apartment complex is reported and the night shift is sent in. Yuri (Rade Serbedzija) the building manager leads everyone and two police officers, James (Andrew Fiscella) and Danny (Columbus Short), to the apartment of Mrs. Espinoza (Jeannie Epper), the source of prior screaming. Yuri knocks, waits, then unlocks the door and a dog runs out. Inside, Espinoza is hysterical, with blood dripping from her mouth and staining her nightgown. While trying to subdue the crazed elder, James gets bitten by Espinoza. The police and firemen save him and leave her in the apartment, with Fletcher to keep watch over her. Lawrence (Greg Germann), a veterinarian, tends to the injured policeman when Fletcher falls off a railing and hits the floor of the lobby several stories below. His neck is broken and his bones are shattered, and there are signs of him being bitten as well, though a pulse is still detectable. Danny and Jake go upstairs, and Jake is forced to shoot Espinoza after she growls and charges at them, even more hysterical than the prior times she is shown on camera. Upon return downstairs, Danny, Jake, Angela, and Scott learn that all exterior windows and doors are sealed from the outside due to a containment process by police officers outside the building; all cell phones and cable connections to televisions are jammed, as well. Everyone except two people, and a sick woman named Elise (Stacy Chbosky) are brought downstairs by the fire department. During a short lull in the action, Angela interviews Briana (Joey King), the five-year-old daughter of two tenants who is sick with bronchitis. Briana reveals that her father took her sick dog, Max, to the animal hospital, which is why he is not around. Lawrence incredulously concludes that the symptoms of those infected are similar to rabies, only much more fast-acting.
Bernard (Bernard White) and Sadie (Dania Ramirez) introduce themselves as a music teacher and his student. In the middle of their interview with Angela, Fletcher, foaming at the mouth, stands up on his broken legs and attempts to attack everyone, but Lawrence sedates him. Bernard, Sadie, Angela, and Scott sneak upstairs to Bernard and Sadie's apartment, where they have a television hooked up to an antenna; without the use of cable television, they will be able to watch the news reports and learn more about what's going on. Upstairs, they witness Espinoza's dog attack a man who refused to come downstairs when he appears in the elevator. Shaken, they continue to Bernard and Sadie's apartment, and watch as a news report on television states that everyone was evacuated from the apartment complex before the police began to quarantine the building, an obvious lie. The power goes off moments later, and a noise is heard from another part of the apartment. Elise, rabid and hysterical, attacks Angela, though doesn't succeed in biting her. Scott beats Elise's face in with the camera, and after a few seconds of letting the moment sink in, the foursome return downstairs, leaving Elise in the apartment, unconscious.
Danny rounds everyone up and informs them that Centers for Disease Control and Prevention agents are coming in to give blood tests. Lawrence corrects him by saying the only way to test for rabies is through a brain sample, but Danny insists on what he was told, refusing to accept that it is rabies. While performing a role call of all the tenants to make sure everyone who is still alive is in the room, Yuri reveals that the attic is being rented by a man from Boston who has been absent for roughly three months.
CDC agents arrive and take a brain sample from Fletcher, who, shortly after, breaks his restraints and attacks one of the agents. Danny, Jake, and the other agent escape, and lock Lawrence in the room with Fletcher the injured man; Lawrence gets bitten. The surviving CDC agent reluctantly explains the situation: an ill dog in a local animal hospital was found to be rabid and attacked all the other animals in the hospital. When they checked the collar, the owner was tracked to live here; the dog is Max, Briana's dog. The tenants all become frightened of Briana and insist that her mother Kathy (Marin Hinkle) allow the CDC agent to run tests on the girl to make sure she didn't catch the illness from Max prior to his being admitted into the hospital. Kathy stubbornly tells them repeatedly that nothing is wrong with her daughter other than a touch of bronchitis, until Briana rapidly shows signs of being rabid and bites Kathy in the neck. She runs upstairs, and Kathy is handcuffed to the stairwell after she tries to prevent them from finding Briana. Danny, Jake, Angela, and Scott bring a needle with sedative and look for Briana in the dark floors above. They find her hiding, and while attempting to inject her with the sedative, Danny gets bitten. Angela, Scott, and Jake run downstairs, terrified.
A few men downstairs fight to contain the infected, but the hungry monsters get them and attack Kathy. Scott, Angela, Jake, Yuri, Yuri's wife, Bernard, and Sadie run into an apartment and lock the infected people out. The CDC agent sitting in an adjacent room reveals that he has been bitten, and it's shown that Sadie was bitten in the hysteria, as well. Bernard, refusing to allow any of the others to shoot her to protect themselves, tears the plastic from the window in an attempt to obtain help. In response, he is shot by a sniper. Yuri remembers that, in his apartment, there are keys to get to the sewers from the basement, but is then attacked by the CDC agent in the other room. His wife is attacked by Sadie, forcing Jake, Scott, and Angela to run to Yuri's apartment in a frantic search for the keys. After they find the keys, Jake and Scott fight off several infected tenants until Yuri bites Jake. Danny barrels up the stairs roaring and chases Angela and Scott into the attic, belonging to the aforementioned absent Bostonian.
They discover evidence - including newspaper articles, a recorded tape, and more - that explains the man from Boston was part of a doomsday cult, which broke into a military biological facility to steal the virus that started everything in the apartment. Scott investigates a noise in the attic and ducks from being attacked by an infected boy, who destroys the light on Scott's camera. Angela and Scott use the night vision setting on the camera to discover an emaciated man (Doug Jones), most likely the man from Boston, as he emerges from another room. He walks past them, just barely getting by without encountering either survivor, but attacks Scott when Angela inadvertently makes a noise. The infected man starts eating Scott, but then hears and attacks Angela, knocking her and the camera to the floor. Angela tries to crawl back to the camera, but is dragged screaming into the darkness.
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