Sam and Dean discover a Colorado small town's darkest secret as a wave of people fall prey to a "ghost sickness" that induces fear, paranoia, and ultimately a fatal heart attack. Sam and Bobby must figure out the cause and cure of the sickness when Dean himself falls prey to it.
Sam and Dean arrive in Rock Ridge, Colorado, pretending to be FBI agents to investigate the death of the marathon runner Frank O'Brien apparently by heart attack despite his good shape. After the autopsy and a couple of interviews, they discover that Frank was lately anxious and jumpy and has died scared to death. Sooner Bobby advises Sam that the three victims in Rock Ridge have died of ghost sickness and Sam realizes that Dean has the symptoms of the disease with intense fear and paranoia. Bobby arrives in the town to help Sam to find the ghost of Luther garland that has spread the outbreak but the time to save Dean is running out.
- Dean is running away from the sound of hell hounds chasing him. He runs into a homeless man and tells him to run, or they will kill him. A terrier runs into view, and Dean flees from it in fear, with the dog chasing.
Sam and Dean are impersonating FBI agents and talking to a coroner about a man, Frank O'Brian, who allegedly had a heart attack. They tell him to do an autopsy, and the coroner finds no blocked arteries in the heart. Dean notices Frank had a wedding ring imprint, and Sam notices scratches on his arms which the coroner states was caused from the fall when Frank died. Dean is asked to hold the heart and Sam gets squirted with "spleen juice" as the coroner is conducting an internal exam.
The brothers go to see the town sheriff, Al Britton, and notice he has an obsession with cleanliness: no shoes in the office and constant use of hand sanitizer. He states that he was Frank's friend and that recently he was jumpy and refused to answer the phone. Later, Sam and Dean talk about how the other victims had scratches on their arms, and when Dean sees some teenagers, he decides to cross the road to avoid them. Sam and Dean go to talk to Frank's neighbor, Mark, who keeps pet snakes and crocodiles, which makes Dean very nervous. Mark explains that Frank was increasingly nervous recently and that he was a bully in school. He states that Frank got better over the years after his wife died 20 years ago. Dean asks if anyone wanted revenge.
Later, Dean is waiting in the car and is startled by Sam, who tells him that Jessie, Frank's wife, killed herself in a hotel and Frank had a perfect alibi the night his wife died. As Dean drives back to the hotel, he stays within the speed limit and refuses to take a left turn into oncoming traffic. Sam picks up the EMF, which is reading waves from Dean.
The next morning Sam calls Bobby and turns to go back to the hotel, only to find Dean in his car listening to "Eye of the Tiger." Bobby confirmed that Dean has ghost sickness, and Sam tells Dean that its basically a contagious disease from a spirit and causes the person to die of fright within 48hrs. The disease spread from Frank to his softball teammates to Dean, who caught it from the corpse. Sam tells him that he has 24hrs left.
The brothers think the ghost was Frank's wife, and Dean admits that he was in the car because the hotel room is on the 4th floor which is high.
Later in their first floor room, Dean is reading up on ghost sickness when he starts to hallucinate that there are insults in the text and begins to see the blood in the pictures more clearly, and the ticking from the clock appears louder than ever. Sam returns to the room to find Dean having broken the clock and sitting on the couch with a beer. Sam tells him that Jessie couldn't be the ghost because she was cremated, and Dean starts to choke on the beer. He goes to the sink and coughs up a wood chip, which Sam to realizes is a clue.
They visit the local lumber mill and Dean refuses to go in until Sam tells him he's his only backup. Dean takes a swig of alcohol. He refuses to take the gun, stating it might go off and tells Sam he'll man the flashlight. Inside the EMF is useless due to Dean, however they find Frank's wedding ring. When Sam opens a locker and finds a cat, Dean screams in terror. Further inside the mill they discover a badge belonging to Luther Garland, an article on Frank's wife, and a sketch of Jessie. The conveyor belt goes off and Dean sees a man standing in the corner. Sam looks and the man turns around, revealing abrasions on his face and body, and begins to walk towards him. Sam shoots him with rock salt and turns to find Dean having run in terror out of the building.
Sam and Dean go back to the station to get the Garland file with Dean hovering drunk in the background. The file states Luther died 20 years ago of physical trauma. The deputy says the death was before his time, and unfortunately Sheriff Britton is out sick. After Sam and Dean leave the deputy tells Britton that the feds wanted the old Garland file. The camera cuts to Britton scrubbing blood on his arms and stating that they know. He hears a voice telling him that they know and he points his gun around the room.
The Winchesters go to see Luther's brother John, who asks to see some identification before he'll speak with them. Sam and Dean hand over their badges and John looks at them as Dean babbles they're real and that impersonating a federal agent is ridiculous. John tells them that Luther was a big man that everyone was scared of and called a freak, yet he was actually gentle and kind. When Sam shows him a picture of Jessie, John tells them that Frank killed Luther. He says that Jessie was the receptionist and nice to Luther, who had a crush on her. When Jessie went missing, before she was found, Frank suspected Luther had done something and went to the lumber mill where he physically beat him, tied an iron chain around his neck, and dragged him behind his truck until he was ripped apart. John tried to get Frank arrested, but nobody wanted to investigate the murder of the town freak.
The brothers realize everyone infected were reliving how Luther died over a period of 48 hours, including the scratches from being dragged down the road, and the wood chip being swallowed along the way. Sam says there is no way to burn the remains as Luther was shredded on the road and they would never find all of him. Dean begins to say they're crazy to hunt monsters and quits. As hes walking away he hears hell hounds behind him...which turns out to be the small Yorkshire terrier.
Dean is back at the hotel and Sam tells him that he's going back to Hell before his eyes turn yellow, and he says eventually he's going to become a demon. Dean is pinned to the wall and starts choking when we snap to Sam shaking Dean out of a hallucination. Sam goes to meet Bobby, who has a Japanese book on spirits and states that Luther is a buruburu, a spirit who infects victims with fear. Bobby says it can be killed by burning, or by scaring it to death. Sam calls Dean to tell him that he and Bobby have a plan and that he should just relax and wait.
Sam and Bobby go to the lumber mill and Dean starts to hallucinate hellhounds trying to break into his hotel room. It turns out to be Sheriff Britton, who comes in with a shotgun demanding to know why they are investigating Luther's death. He defends Frank, his friend, who he refused to arrest for murder. They tussle and Dean manages to knock the gun away and throw Britton off him onto the ground. Britton cowers in fear and suddenly dies.
When Luther doesn't come out in the mill, Sam rips up pictures of Jessie to anger him. He turns around to find Luther standing there and is grabbed by the throat and thrown to the ground. Dean is sitting on the bed and continues to hallucinate as the scratches grow. He picks up the Bible and sees Lilith, as a little girl, appear on the bed next to him. She tells him he's going back to Hell and asks if he remembers all the fun down there. Lilith tells him he's going to die. Dean asks why it has to be him, and she tells him to listen to his heart.
At the mill Sam tries to get to the shotgun but is yanked away. However he manages to wrap a chain around Luther's neck and tells Bobby, who is in the truck, to step on it. Luther is pulled away by the chain around his throat and is dragged behind the car. In the hotel room Dean is still hallucinating Lilith who says "boom boom, boom boom!" making his heart race faster and faster. The camera cuts to Bobby towing Luther, to Dean, then back to Luther dragging on the ground until he disintegrates and Dean's heart stops pumping so hard.
Later the guys are sharing a beer and Sam explains the chain was made out of iron. Dean is back to himself and Bobby heads back home. Sam asks Dean what he hallucinated in the last few minutes and Dean says howler monkeys, nothing he couldn't handle.
The credits begin to roll and there is a bloopers scene with Jensen Ackles doing air guitar and lip-synching to "Eye of the Tiger." He begins in his car and ends up standing on top of it.