Cherry Darling (Rose McGowan) works as a gogo dancer at a club. After crying onstage one more time, she decides to make a real change and quits her job. While walking home, several military lorries pass her very close so she has to throw herself into a bunch of dustbins and gets some big splinters on her thigh.
A car stops at a barbecue restaurant and Tammy (Stacy 'Fergie' Ferguson) comes out and asks for some water for her car's overheated engine. At this same place, Cherry is cleaning her wound and after that, she sits down inside the restaurant.
At the military base a couple of miles away from the town, scientist Abby (Naveen Andrews) is threatening his employee Romey (Julio Oscar Mechoso) for having lost three very valuable 'specimens' and finally has his testicles torn off. Lt. Muldoon (Bruce Willis) shows up, wearing a gasmask. He asks where 'it' is. Abby answers it is everywhere-- several containers full of a green hazy gas have broken, and the green mist is spreading in the air.
Dr. William Block (Josh Brolin) and Dr.Dakota Block (Marley Shelton) wake up. Through their window, they can see the eerie green mist. Dakota makes breakfast for her husband and son, Tony (Rebel Rodriguez) and texts her lover to pick up Tony who will be with the babysitter.
Back in the barbecue restaurant, El Wray (Freddy Rodriguez) comes in and chats with JT Hague (Jeff Fahey), who is celebrating his restaurant 25th anniversary, and is obsessed with having the best barbecue in Texas and winning a contest. El Wray comes over to where Cherry is sitting and we learn they used to date. Cherry tells him she is actually a stand-up comedian instead of a gogo dancer.
In the hospital where Bill and Dakota work, people with strange symptoms start coming: the first one, Joe (Nicky Katt), has a bite supposedly half an hour old with an advanced stage of gangrene and viral and bacteria infection. The only treatment is amputation. Dakota comes over and gives the patient some anesthesia. Dr. Felix (Felix Sabates) notes he has seen similar wounds before in Iraq soldiers, due to mustard gas.
El Wray drives Cherry home, but on their way they are attacked by some zombie-like creatures who take Cherry away and pull off her right leg. El Wray scares them away and takes Cherry to the hospital. At the same time, Stacy's car breaks down and while she is walking down the road, three zombies attack her. At the hospital, the Sheriff (Michael Biehn), takes El Wray away for having used a gun after having his gun license removed. Tammy's corpse has been retrieved and her brains have been completely eaten out. Bill takes Dakota away and we learn that actually Tammy was Dakota's lover. Bill goes berserk and repeatedly stabs his wife on her hands with an anesthesia needle.
Back with the sheriff, Deputy Tolo (Tom Savini) complains about some maniac biting his finger off-- literally. JT calls the sheriff to complain about two wreckers outside his restaurant. His brother tries to get the barbecue recipe from him. Outside they see three zombie-like people and after a short fight the sheriff and his deputies kill them and head off towards the hospital with El Wray in his wreckage lorry. Total mayhem has taken over the hospital, where the infected corpses and injured are chasing and attacking both doctors and patients. Doc Block becomes infected by Joe, who breaks a sore open and rubs the bloody pus onto his face. El Wray gets to where Cherry is, soothes her, sticks a piece of wood in her stump to make her a new leg, and rush out of the hospital.
Dakota Block takes profit of the chaos and sneaks out of the hospital, then tries with great difficulty to get in her car and drive it, because her hands are numb. At her place, the Venezuelan twin babysitters complain about the delay and are kicked out of the house. Dakota takes Tony to his father's Earl McGraw (Michael Parks), whose cancer-ill wife had been infected too so Earl was forced to kill her. Dakota leaves Tony in her car with a gun and tells him to shoot anyone who comes close except for her, warning him not to point at himself. Unfortunately, as soon as she leaves, he shoots himself. Dakota takes her son's corpse and hides into her father's.
The sheriff, with his deputies, Cherry and El Wray head to the barbecue restaurant, where JT had been apparently killed by a couple of zombies but resulted to be only making a practical joke. Cherry and El Wray rest in JT's bedroom and have sex. Every survivor results to have found shelter in JT's restaurant, including the twin sisters, Earl McGraw and Dakota, Cherry's former boss and some other people. They all agree to flee from the town riding every car and motorcycle they can use.
Near the military base, they are blocked by a wall of zombies, which are killed by a bunch of soldiers hidden beneath. We find out El Wray is actually a war veteran. They take the survivors as prisoners, and while trapped they find Abby, who explains he is a scientist and businessman who sells this mortal virus, DC2, to this soldiers, who need to inhale it constantly as the only way to control the disease, as there is no cure. The rapist soldier (Quentin Tarantino) comes over to Cherry and Dakota and takes them away. JT gibberishes about barbecue sauce to distract the soldiers' attention so that El Wray and Abby can break their way out. They get to Lt. Muldoon who explains what it is actually happening.
He and his soldiers in Afghanistan managed to get to the most wanted, Osama Bin Laden, and killed him. But as this was against America's interest, instead of medals they got DC2, a chemical weapon designed to wipe out entire cities. As he had promised his men a cure which was still unknown, one way to find it (with Abby's help) was spreading it over a whole town and then taking the survivors to extract a cure from them. During this whole speech he has not been wearing his gasmask, so he is swollen and blistered and finally gets killed by El Wray.
Meanwhile the rapist soldier is trying to do so to Cherry, forcing her to dance on her wooden leg, but for the same reason, not wearing his gasmask, gets swollen and ill and his crotch starts to melt and fall apart. Cherry stabs him with her wooden leg in one eye and Dakota shoots a needle like a dart right in his other eye. Abby and El Wray arrive and kill the rapist and his partner and go back to fetch the others, except for the sheriff and JT, who had both been fatally injured before. They take care of a bomb to destroy the base after everyone is out. El Wray sticks a specially crafted custom-made M4A1 carbine assault rifle/M203 grenade launcher into Cherry's stump.
The survivors force their way through the soldiers to a couple of hellicopters using Cherry's new leg and their own guns. On their way, Abby gets killed and Dakota is attacked by Doc Block in zombie state coming out of nowhere, and then shielded by her father. El Wray gets killed trying to protect Cherry and after dying encourages Cherry to carry on, lead their resistance, flee to Mexico and raise the child he is sure she will have. Dakota gets Cherry in her hellicopter and she unwillingly leaves El Wray.
The next thing we see is Cherry, with an upgraded gattling gun for a leg, riding an animal, carrying her and El Wray's daughter, leading the survivors through Mexico, protecting them from the infected which seem to be now everywhere.
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