After Sam released Lucifer from his Cage, the Four Horsemen of the Apocalypse became active and began performing their duties in the Apocalypse. As part of this, Pestilence began spreading a mild case of swine flu across the country so that Niveus Pharmaceuticals would create a vaccine and distribute it with the "vaccine" really being the refined Croatoan Virus which he intended to spread. While this was going on, Pestilence also based himself as a doctor at the Serenity Valley Convalescent Home and began experimenting on the patients with combining diseases for greater effect.
While searching for a way to defeat Lucifer, Sam and Dean Winchester got a message from Gabriel that told them that the key to locking Lucifer back in his Cage was the rings of the Four Horsemen of the Apocalypse. Having already gotten War and Famine's rings, the Winchesters began to focus on Pestilence and Death. With the help of Crowley, they captured the demon Brady who headed Pestilence's plot at Niveus. They managed to force Brady to give up Pestilence's location before killing him. Shortly before they leave for the convalescent home to confront Pestilence, Sam and Dean hear from Castiel for the first time since the fight to rescue Adam and learn that he is now human. They inform him of what they are up to and have Bobby wire him money so he can meet up with them.
Sam and Dean arrive at the convalescent home, but don't know who's human, who's a demon and who's Pestilence so they knock out a security guard and use the security camera system to look for clues. Eventually they spot a man who's head is distorted in the camera view and realize he must be Pestilence. As they start to go after him, Pestilence's assistant notices them and warns Pestilence of their presence and that they should leave. However, Pestilence is enraged by what they did to his brothers and decides to take it out on them despite Lucifer's orders to leave them alone. Pestilence unleashes his power into the convalescent home, killing all the doctors and patients and causing Sam and Dean to collapse before they can reach the room Pestilence is in and stop him.
Pestilence's assistant drags Sam and Dean into the room and Pestilence taunts them with the combination of diseases he has infected them with as Dean tries to reach the demon-killing knife to cut off Pestilence's ring, the source of his powers and what they need from him to lock Lucifer back up. However, Pestilence prevents him from getting the knife, but as he taunts them, Castiel arrives to help, having taken a bus due to his lack of angelic powers. However, as he is no longer an angel, Castiel falls under Pestilence's influence and collapses too. Pestilence taunts Castiel about his lack of power, but Castiel still has just enough angelic strength left to resist Pestilence's power long enough to grab the demon-killing knife off the floor and cut off Pestilence's ring and pinky fingers, defeating him. Pestilence's assistant attacks Castiel, but Castiel kills her with the knife. Before disappearing, a defeated Pestilence tells Sam and Dean that their victory doesn't matter and that "its too late", leaving them worried about what he means.
After getting Pestilence's ring, Sam, Dean and Castiel return to Bobby's where they worry about what Pestilence meant with his last cryptic statement. While they're trying to figure it out, Bobby informs them of his deal with Crowley which has allowed them to locate Death. As the Winchesters prepare to go to Chicago to face Death, Crowley shows them a newspaper stating that Niveus Pharmaceuticals is stepping up its distribution of its swine flu vaccine. As Pestilence's demon minion Brady was in charge of distribution and Pestilence was spreading the swine flu, the Winchesters realize that what Pestilence was referring to when he told them that it was too late, was he was using the so-called swine flu vaccine to spread the Croatoan Virus across the country simultaneously.