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When a virus causes a large portion of humanity to become uncontrollably violent, Deacon, his wife Sarah (Courtnee Draper), and his friend Boozer (Jim Pirri) attempt to flee for safety and escape the carnage. Sarah is stabbed and critically wounded, forcing Deacon to evacuate her on a National Emergency Response Organization (NERO) helicopter. Due to the helicopter being at capacity, Deacon stays behind with Boozer, intending to reunite with Sarah.

Two years later, civilization has collapsed, and vast hordes of the infected, now called "Freakers", roam the landscape and are a persistent threat to surviving humans. Deacon and Boozer work as freelance bounty hunters in what is left of Oregon, with Deacon believing Sarah is dead after finding out the NERO refugee camp she was evacuated to was overrun by Freakers. Deacon and Boozer plan to head further north to find better opportunities, but Boozer has his arm badly burned by a gang of cultists called Rippers, forcing him to stay at their safehouse to recuperate and delay their trip. Deacon learns the Rippers have placed a price on his and Boozer's heads. In addition, Deacon catches sight of NERO helicopters carrying a research team several times, leading him to believe there is a chance Sarah may be alive. He manages to track down and confront one of the NERO researchers, James O'Brian (Bernardo de Paula), who evacuated Sarah. He reveals that his helicopter was diverted to a different camp mid-flight, rekindling Deacon's search.

Boozer's health begins to decline rapidly from his burn wounds, forcing Deacon to take him to the Lost Lake camp for medical treatment. Boozer has his arm amputated due to an infection. O'Brian contacts Deacon, requesting his help in investigating what NERO is researching in return for helping him track down Sarah. Meanwhile, Lost Lake has an uneasy nonaggression treaty with the Rippers, held up by Lost Lake's leader Iron Mike (Eric Allan Kramer) while his lieutenant Skizzo (Jason Spisak) is skeptical of Rippers' willingness to honor the treaty. Skizzo makes a separate deal with the Rippers and turns Deacon over to them, where it is revealed that the leader of the Rippers is Jessie Williamson (Scott Whyte), an old enemy of Deacon and Boozer. Deacon escapes custody and, together with Boozer, drowns the Rippers by destroying the dam above their camp and kills Jessie. Skizzo is exiled from Lost Lake for his betrayal.

Later, Deacon remembers that Sarah worked at a government lab and would have had a federal security clearance, meaning she would have been a priority to evacuate from the camp. O'Brian confirms that Sarah was evacuated to a military outpost at Crater Lake, but th
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