|Dean walks down a corridor with a gun, then goes into a room with a sign mentioning River Grove on the wall. Several people are there and a man says its not in him. A doctor is present and says she can't tell for sure. Dean aims the gun, and fires and Sam wakes up from his vision-dream.
Dean and Sam drive to River Grove while Dean wonders how the dream relates to the yellow-eyed demon. They roll into town and ask an ex-military man, the Sarge, about the man Dean saw in his vision. They get directions to the man, Duane Tanner, and Dean notices the word Croatoan carved on a board. Dean notes how a similar word was found at the Roanoke colony in America and it was wiped out overnight. They try to call out but cant get a cell signal and the pay phone is dead.
They go to the Tanner house and talk to Duane's brother Jakeand hisfather, but Duane is on a trip. The two act strange and afterDean andSam leave, they double back and see Mrs. Tanner tied up inthe kitchenas her son and father prepare to cut her and mingle theirblood withhers. Mr. Tanner comes at them and they're forced to shoot,and whenSam hesitates, Duane runs into the woods.
The brothers take Mrs. Tanner to the local doctor, Lee, andshe triesto explain how her son and husband had the devil in them.The Winchesterswonder if demon possession is involved, but there wasno blacksmoke. Dean drives to go get help but finds a car with a bullet through the windshield. It's filled with blood and there's a knife nearby, but no bodies.
Dr. Lee examines Mr. Tanner's body and determines he was fighting off some kind of infection. There are also traces of sulphur. On the road, Dean keeps driving and comes to an improvised blockade lead by Jake Tanner. They tell Dean there's a quarantine in place and askhim toget out of the car, and Dean drives off as they open fire.
Dr. Lee tries to take a sample of Mrs. Tanners blood, but shegoes berserkand attacks them, and Sam is forced to knock her out with afire extinguisher. Dean drives through town and runs into theSarge fromearlier. After a tense standoff, they determine they're both unpossessed and head for Dr. Lee's office. Her nurse, Pam insists ongoing out to find her boyfriend but Sam convinces her to stay. Deanand theSarge arrive and Sam tells his brother that their father suspected Croatoan was the name of a plague-demon. Sarge warns thathis neighborsgot stronger the longer they were infected, and they haveto killMrs. Tanner. Dr. Lee doesn't know of any way to cure her andthey goin, but Mrs. Tanner is apparently normal. She doesn't foolthe brothersand Dean shoots and kills her.
The group tries to plan a defense when an apparently uninfected Duane arrives. He claims he fought off the other infected people but Dean notices he has a cut and they tie him up. Dr. Lee notices there's no way to determine if he's infected until after he is possessed.Sam warnsDean that his vision is coming true and that his brotheris actingincreasingly violent. Dean locks Sam up and then goes to shoot Duane. Dean considers it but in the end can't bring himself to do it. He lets Sam out and they prepare explosives from the medical supplies. Dr. Lee has had enough time to determine Duane is clean and theyuntie him. Pamela manages to get Sam alone for a minute and attacks him, mixing her blood with his through a cut. Dean shoots and kills her, but Sam is now infected.
Dean refuses to shoot Sam but Sam offers to kill himself.Dean stillrefuses and gives them the Impala keys so they can escape.After theyleave, Dean admits he's tired of the job and starts to talk about John, but Dr. Lee returns and interrupts them. It's night outsideand everyonehas vanished. Five hours pass and Dr. Lee determines that Sam's blood is clear. Lee checks the Tanner samples and determines there's no trace of the virus. Duane and Sarge head south whileSam wonderswhy he was immune. Later on the road, Duane asks the Sargeto pullover to make a call, then cuts the Sarge's throat and collects his blood in a familiar goblet. Duane reports that no further tests are necessary and Sam is immune as they suspected.
Later Sam and Dean take a break and Sam insists that Dean tellhim whathe was going to say before he was interrupted. Dean says thathe promisedJohn not to say anything but says that John told himsomething aboutSam.