In 1968, an infected man from Russia, Rubinsky, is being operated on at a military hospital when soldiers arrive and begin to shoot all of those who are in the building. One of the hospital students, DeLuca, steals a strange vial, enclosing it in his thermos. He is later shot by the soldiers as he attempts to escape through the woods and the thermos is dropped. The soldiers in the hospital continue to kill any one that has been in contact with the infected man. Zombies kill three of the soldiers and multiple hospital orderlies. The rest of the zombies are killed when C4 is detonated by sharpshooters outside the hospital.
Thirty-seven years later, in 2005, a group of patients at the same hospital from 1968, consisting of Boris, Jackie, Isaac, Sam, and their doctor, Donwynn, uncover a strange thermos buried in the soil in the yard of a hospital. Sam attempts to open it, but they are unable due to it being rusted shut. Donwynn entrusts Sam with keeping it safe, but Isaac feels that something bad will happen if the thermos is opened.
While Sam and Boris are distracted with watching a movie, Jackie sneaks away with the thermos and runs to the bathroom to open it. Isaac and Emma have a romantic encounter (under supervision of Donwynn), but Marshall, an orderly, attacks them. Marshall and Donwynn take the two back to their dorms for the night. Emma escapes Marshall's grasp and runs to Isaac's dorm, while Marshall is dealing with Patty, one of Emma's friends. Sam discovers that Jackie stole the thermos, and with Boris, Isaac, and Emma, they go to the bathroom to talk him out of opening it. Jackie opens the thermos, and a strange object falls from it, unknowingly releasing a virus, infecting the entire group.
Doctor Heller talks to Donwynn about his patients’ behavior, while Marshall and other staff take them back to their dorms. He claims that Jackie and the other students are breaking the rules of the hospital, while, in truth, they aren’t. Emma, Patty and Vicky are locked in padded rooms for their “behavior.” That night, those who were in the bathroom begin to show signs of sickness. Donwynn contacts a friend, Jerry, by email about the item that was in the thermos, hoping to get an answer as to what it is.
The next day, Donwynn awakes to discover Sam having a seizure and the rest discover that they all have skin on their bodies that is dead and peeling. Emma, namely due to her “encounter” with Isaac, has tests ran on her, and she is told that she is pregnant (due to the virus). Emma attacks Marshall when he keeps bothering her about the results of her test, and she bites him on the arm, infecting him. Sam, Jackie and Boris begin to show advanced signs of infection, including rotting flesh, varicose veins, and coughing up blood. Marshall is quarantined because of the infection from the bite. Dr. Heller puts the hospital under a full quarantine and gives the doctors the right to bear arms, along with orders to shoot anyone from Dorm 1 in the head that attacks them. Donwynn receives a video reply from Jerry, who tells him not to open the thermos because it contains a deadly virus that mutates human DNA. Donwynn informs Sam that he plans to visit the hospital the next day. Marshall dies of his infection that night.
The next morning, everyone is called to the front desk of the hospital to receive a vial of medicine. Ava informs Donwynn that the virus is flesh-eating and kills its host. Patty and Vicky get into a fight, which is broken up by Derber. Pete senses that Donwynn smells dead, and goes crazy. This gives Patty a chance to steal one of Derber’s handguns, and escape to see Emma. Patty shoots and kills one of the security guards in order to open Emma's room. Marshall reanimates as a zombie and kills Dr. Heller, who has stopped in to study the advancement of the infection. Donwynn has jumped out of a window to try to find out why the hospital is quarantined, and observes the killing of Heller. While trying to find Emma, Patty shoots Isaac, but he revives and is unharmed. Marshall breaks free from his cell and kills a security guard.
Jerry arrives at the hospital just as Donwynn returns to the hospital, and informs the patients of what the virus truly is, and how it works. He also reveals that each of them are dead “by human standards.” Jerry also reveals that those infected with the virus are highly contagious, and informs the patients of how the virus was first released. The zombified Marshall is shot to death by the hospital’s police force. Jackie attacks Jerry and slams his head into the door, opening a wound. Boris, no longer able to contain his blood lust, mutates into a zombie, and bites Jerry, causing Jackie and Sam to attack him as well. The three devour him while Isaac, Donwynn and Emma run to the doctor's office, outside of the dorm. Jackie, Sam and Boris have completely turned to zombies and they taunt the surviving patients from inside the dorm.
Early the next morning, Dr. Heller has reanimated as a zombie. He enters the room where Vicky is hiding, but he is distracted by the infected Charlie who he chases away. The patients in the dining room all reanimate as zombies and begin to devour the police officers. The survivors escape into the kitchen of the hospital, but are forced to retreat into the back hallway. Patty finds Vicky in the medical room, and kills her while searching for Emma. The majority of the zombies escape from the hospital and head out into the city. The survivors manage to reach the medical room, where Emma goes into labor and the last police officer is killed. The zombies begin to kill people in the city, Charlie among the victims. Boris, Jackie and Sam break into the room, attacking Isaac, Emma and Donwynn, trying to convince them that they don’t want to hurt any of them, they just want them to turn and be a family. Boris kills Ava, and Isaac, in the later stages of the infection, commits suicide with the last round of a pistol. The movie ends with the zombies attacking a camera crew recording the carnage.Justin Ipock as IsaacLaurie Maria Baranyay as EmmaJohn F. Henry III as JackieJulian Thomas as SamStephan Wolfert as Doctor DonwynnSteve Colosi as BorisSamantha Clarke as Ava FloriesApril Wade as PattyJoe C. Marino as MarshallJackeline Olivier as VickyAndreas van Ray as Doctor HellerKevin Wetmore, Jr. as JerryRuss Kingston as The InfectedSimon Burzynski as RubinskyMike Dalager as DerberChristopher Estes as CharlieRebuka Hoye as Linda
Day of the Dead 2: Contagium completed shooting in Los Angeles in April 2004. The co-directors said that production had been kept quiet in order to avoid media attention while filming.
A ten-minute promotional reel screened at the 2004 Fantasia International Film Festival, where it was not well received. It played at the 2004 London FrightFest Film Festival, after which Starz and Anchor Bay Entertainment released a special edition DVD on October 18, 2005.
Writing in The Zombie Movie Encyclopedia, Volume 2, academic Peter Dendle called it a "boring, transparent feature" that was "forgotten almost as soon as it was released". Steve Barton of Dread Central rated it 0/5 stars and wrote, "This is a sequel in name only, created solely to generate revenue from ill informed fans." Joseph Savitski of Beyond Hollywood wrote that the film "is not only an exercise in incompetence, but also a blatant attempt at false advertising." Dennis Prince of DVD Verdict wrote, "There is no warning too strong that would urge you to avoid this DVD at all costs."