Dr. Owen (Jonathan Mellor), an official from the Ministry of Health, and a Grupo Especial de Operaciones (GEO) team equipped with helmet-mounted video cameras are sent into a quarantined apartment building to control the situation. After encountering some of the infected, Owen uses religious mantra and rosary to fight them off. It turns out that Owen is actually a priest sent by the church to get a blood sample from the Medeiros girl and aid the other priest in charge of her.
When they get to the penthouse, they find out that the infected can travel all around the building through the air ducts. The Medeiros girl is nowhere to be found. Larra (Ariel Casas), one of the GEO officers goes into the air duct and finds a sample of her blood the only one that the original priest took from her. Owen then performs a religious rite, and the blood spontaneously combusts, confirming that it is the blood he's looking for; however, the rest of the blood also sets on fire and Larra drops it, rendering it useless. They must then get a blood sample from the Medeiros girl herself.
Jennifer's father (Pep Molina), who was outside getting medicine for his daughter (the infected girl from REC), manages to convince a firefighter to take him into the building. Moments before the building is quarantined, three teenagers named Tito (Pau Poch), Mire (Andrea Ros) and Ori are messing around on a roof. When the police quarantine the building, they find them and escort them out to the street. The teenagers gain access to the sealed building through the sewage system; however, police have seen them and seal their exit. Inside, the teenagers find Jennifer's father and the firefighter.
After some deaths from attacks by the infected, the two groups find each other. Then the group finds Angela Vidal (Manuela Velasco), the reporter from REC. She has her camera with her. Tito gets bitten by the infected, and they restrain him. Owen then forces him to tell him where the Medeiros girl is. The demon possessing Tito tells him that she is "in the highest." Owen figures out that this means that she is in the penthouse. The GEO team leader, argues that they had already cleared that area and did not see anything. The demon then gives a hint that the "light" blinds them from seeing the path. When Angela was asked how she saw the Medeiros girl, she said she saw it through the camera's night vision. Owen deduces that some things can only be seen in the dark. Before leaving, they lock Mire and Ori in a room for protection.
Finally, they go back to the penthouse. When they turn on the camera's night vision, a door appears that leads them to a room. Inside that room and with the lights off, they finally find the Medeiros girl. After some struggling, Angela blows Medeiros' head off with a shotgun. Owen is enraged because he needed the blood sample, but all Angela wants to do is leave the building. At this point, the only survivors left are Angela, Owen, and Rosso (Pablo Rosso), a GEO officer. When Owen refuses to authorize their exit, Angela starts to beat him to force him to do so. Rosso tells her to stop, but she shoots and kills him. Then it is revealed that the Medeiros girl has possessed Angela, so she can left the darkness she was trapped in, and consequently the building. After telling Owen that she does not need him to get out as she can impersonate his voice, she kills him. She takes his radio and, using Owen's voice, says that the mission is over and that they can let them out. She also tells them that he is staying behind because he is infected and the only survivor is a woman, Angela. When asked how the woman survived, Angela leans towards the camera and smiles.
The ending of the original film is shown. Angela is dragged by her feet into the dark but manages to crawl back into the camera's view. The Medeiros girl quickly gets on top of her. Then she inserts a worm-like organism into Angela's mouth. Then she hears the GEO team and Owen, and she goes into hiding, marking the beginning of the film.