Three years after The Rising began, Vanessa - a mysterious dead woman - is resurrected in a world now ruled by vampires. Holed up in an abandoned hospital with other human survivors, she fends off both vampires and treacherous humans and discovers special powers even she didn't know she had.

In the days leading up to The Rising, Vanessa is attacked and left for dead by an intruder. When Doc discovers anomalies in Vanessa's bloodwork, Axel and the marines come to retrieve the body, only to become marooned in the hospital when The Rising erupts outside the building.

When the hospital's power source is damaged, Vanessa and the survivors only have three hours of reserve power for the UV lights - the only thing keeping the vampires at bay. While Vanessa and Axel head into the ruins of Seattle to scavenge parts, the others are left to fight: against both vampires and amongst themselves.

Vanessa and Mohamad head into the vampire-controlled streets in search of Dylan, the daughter that Vanessa orphaned when she died. Back at the hospital, Cynthia is found dead. Doc soon discovers that what looked like a suicide is actually a deliberate murder. Is there a killer amongst the group? On their return to the hospital, Vanessa is captured by vampires while Mohamad leads a new group of refugees to the hospital.

Vanessa, now in the clutches of Julius and his vampire brood, is forced to demonstrate her powers against someone from her past. Afterwards, she escapes, jumping from the frying pan into the fire. Meanwhile, the refugees discover a serial killer among the other residents, and plot to wrestle control from Axel. In the aftermath, Mohamad is banished from the hospital.

Vanessa and Susan are pursued through the sewers by mutated feral vampires and arrive back at the safety of the hospital only to find the aftermath of a hostile takeover. Vanessa hatches a plan to take it back by force.