Season 1: Lincoln Burrows (Dominic Purcell) is accused of murdering Terrence Steadman (Jeff Perry), the brother of the Vice President of the United States. Because of convincing evidence, Lincoln is sentenced to death. He is incarcerated in Fox River State Penitentiary where he awaits his execution. Lincoln's brother, brilliant structural engineer Michael Scofield (Wentworth Miller), is convinced of Lincoln's innocence and formulates an escape plan. In order to gain access to Fox River, Michael commits armed robbery and receives a five year sentence. While incarcerated he must race against the clock and make important connections with other inmates and staff. One staff member in particular is the prison doctor, Sara Tancredi (Sarah Wayne Callies). Michael befriends her when he pretends to suffer from Type 1 diabetes in order to gain daily access to the prison's infirmary. The brothers' fight to ward off the execution is aided by their lifelong friend Veronica Donovan (Robin Tunney), who begins to investigate the conspiracy that put Lincoln in jail. However, they are hindered by covert agents, members of an organization known as The Company. The Company was responsible for framing Lincoln, and they did so because of Lincoln's father, Aldo Burrows, and his former connections to the company. The brothers, along with six other inmates, Fernando Sucre (Amaury Nolasco), Theodore "T-Bag" Bagwell (Robert Knepper), Benjamin Miles "C-Note" Franklin (Rockmond Dunbar), David "Tweener" Apolskis (Lane Garrison), John Abruzzi (Peter Stormare), and Charles "Haywire" Patoshik (Silas Weir Mitchell) who come to be known as the Fox River Eight finally escape in the season finale because of the help of Dr. Sara Tancredi who has been convinced by Michael to leave the infirmary door unlocked. Because of her involvement, Sara overdoses on morphine.
Season 2: It begins eight hours after the escape, focusing mainly on the escapees. Series creator Paul Scheuring describes the second season as "The Fugitive times eight" and likens it to the "second half of The Great Escape". The fugitives split up and journey to locations across the country with the authorities close behind them as they each pursue their individual goals. Brad Bellick (Wade Williams) gets fired from the prison where he worked as a guard in season 1 and chases after the inmates himself for the reward money . Several of the escapees reunite in search of a large cache of money buried long ago by another prisoner who is rumored to be D. B. Cooper. T-Bag manages to escape with the money, and the brothers spend the rest of the season tracking him down, both for the money which they need to escape the country, and because Scofield feels responsible for releasing the murderer.
Federal agent Alexander Mahone (William Fichtner) is assigned to track down and capture the eight fugitives, but is revealed to be working for The Company; The group wants all eight men - especially Lincoln - dead. Several of the escapees are killed or recaptured, but the brothers make it to Panama. During the brothers' flight, Sara's father, Governor Frank Tancredi, is murdered because he discovers the truth behind Lincoln's innocence. After discovering him dead, Sara returns to her apartment only to have to flee for her life. She meets up with Michael on two different occasions, remaining with him as the brothers try to bring down the current President, a Company member. To ensure the brothers' safety, Sara allows herself to be arrested and faces a trial. During the trial, the testimony of a former Secret Service agent, who used to work for the Company-controlled President, exonerates Lincoln and Sara. Meanwhile Michael, T-Bag and Mahone are arrested by the Panamanian authorities and are imprisoned at the Penitenciaría Federal de Sona where they find Bellick who had been arrested earlier that episode.
Season 3: The season follows both Michael inside Sona and Lincoln on the outside. Sona is a prison that has been run by the inmates and guarded only from the outside since a riot the year before. Burrows is quickly contacted by The Company who have kidnapped his son LJ (Marshall Allman) and Sara Tancredi (Sarah Wayne Callies), the woman Michael loves. He is told that they want Scofield to break James Whistler (Chris Vance) out of Sona. The season follows Michael and Whistler's trials in formulating an escape plan, as Michael has to deal with extreme tension and as Lincoln deals with the Company's operative Gretchen Morgan (Jodi Lyn O'Keefe). Sucre gets a job at the prison to aid Michael in his escape plan.
When Lincoln attempts to rescue Sara and LJ following a clue provided by Sara, Morgan "beheads Sara" and sends Lincoln a head in a box as a warning. As the season ends, the pair manage to escape along with Mahone leaving behind several accomplices including T-Bag and Bellick. Sucre's identity is discovered by a prison guard and is thrown into Sona just after the escape. LJ is traded for Whistler, and Michael is out for revenge against Gretchen for "Sara's death".
Season 4: While avenging Sara's death, Michael learns that Gretchen did not kill her as he thought. Michael also learns the truth about Whistler, that he has secretly been working alongside Mahone to take down the Company. A Company operative takes Whistler's life shortly after this. Sona has burned down and Sucre, Bellick, and T-Bag have escaped during the chaos. After returning to Chicago to look for Sara, Michael is arrested and recruited by Donald Self (Michael Rapaport), a Department of Homeland Security agent, to help bring down the Company in exchange for his freedom. Lincoln, who was arrested in Panama is transferred to Chicago, and along with Mahone, Sucre, and Bellick a deal is made. Also joining the group are Sara, who escaped from Gretchen which resulted in Gretchen's own captivity by the Company, having failed to secure a valuable item, and Roland (James Hiroyuki Liao), a hacker who was assigned to help them after getting arrested for identity theft. Together, they devise a plan to retrieve Scylla, thought of as the Company's 'little black book', from the Company that will help to destroy them. In the meantime, Wyatt (Cress Williams), an agent from the Company, attempts to track Michael and Lincoln down and T-Bag heads North to the US with the "Birds" book in his possession. Michael also begins to experience some troubling health problems.
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