Dean frantically runs down a dark street chased by something making a growling and barking sound. Dean crashes into a homeless man and tells him to run for his life before it gets him. The homeless man looks at Dean, then looks down at what's chasing him which is a small dog with a pink bow.
The show flashes to 43 hours earlier. Sam and Dean arrive at a small town to examine the circumstances behind the death of Frank O'Brien. Posing as FBI agents, the brothers meet with the coroner and asks him to perform an autopsy. They notice strange gashes on Frank's arm and see a mark on his finger that indicates he was wearing a wedding ring, but it's now missing. The coroner tells the brothers that Frank was an otherwise healthy man who suddenly died from a heart attack. When the coroner pulls out Frank's heart, he finds it is in good condition. He asks Dean to hold the heart while he looks for more clues. Sam is squirted in the face with fluid. After inconclusive findings, the brothers leave.
Sam and Dean go to the police station and talk to Al the sheriff. Al shakes their hands, then pours sanitizer all over his hands. He tells them that he was friends with Frank and that they played baseball together. They ask Al if Frank was acting strangely before he died. Al says that Frank became jumpy and stopped answering his phone. Al sent his guys to check in on him and that's when they found he was dead. The sheriff tells them that Frank's neighbor was the last person to see him alive.
Sam and Dean exit the police station. Dean is nervous about a group of teens that he thinks look menacing. The brothers then go to Frank's neighbor, a man with many reptiles, including a large snake he wears around his neck. The neighbor says that before he died, Frank was freaking out about witches after he saw The Wizard of Oz. He says Frank thought the witch from the movie was out to get him. He also tells the brothers that Frank was a bully in high school, but he got better. The brothers ask if anyone would have wanted to kill him and the neighbor says no. He then tells the brothers that Frank used to be a dick, but after his wife Jessie died 20 years ago, he became less of a jerk.
The neighbor notices Dean looking at his creatures nervously. He tells him not to worry about the snake around his neck, but to watch out for the snake crawling up behind Dean because she smells fear. The brothers leave and Sam checks out Frank's house. He says it's clean and there's no evidence of ghosts. He finds Dean scratching his arm in the car.
The brothers drive away and Sam notices Dean is only driving 20 mph. Dean then misses the left turn into the hotel driveway because he says he didn't want to turn left into oncoming traffic. Sam goes up to the hotel room and Dean waits in the car.
Sam returns to find Dean lying down in the car rocking out to Eye of the Tiger. Dean stops and shows Sam some scratches on his arm. Sam tells Dean that he called Bobby for help with the case and Bobby told him that it sounds like Ghost Sickness. Sam explains that a ghost can infect a person with a virus that causes anxiety, then extreme fear, then death in 48 hours. Sam tells Dean that he has symptoms of the illness. Dean tells him he hasn't been around any ghosts, but Sam says that it can be transmitted from human to human after the initial ghost infection. He thinks Dean caught it during the autopsy. Dean asks why Sam wouldn't have the sickness too since he was squirted in the face. Sam then tells him that people who come down with the illness all share a similar personality, they're all dicks. Dean tells Sam he's a dick too, but Sam say's apparently he's not.
Dean is frightened knowing he only has 48 hours to live. Sam corrects him and says since he was infected yesterday, he only has 24 hours. Now afraid of heights, Dean gets Sam to relocate their fourth floor room to the first floor.
Dean studies up on the ghost sickness. He reads that the person begins to hal