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Season 2 consists of a total of 22 episodes and was first aired from August 21, 2006 to April 2, 2007. It directly follows the prison break from the first season. A new major character is introduced, who is FBI Special Agent Alexander Mahone, portrayed by William Fichtner. The first half of the season revolves around the escapees' journey to their family, Westmoreland's money and Michael's plan to escape the country. The second half of the season focuses on the conspiracy plot of the series. The season's plot spans approximately three weeks of the characters' lives.
- Dominic Purcell - Lincoln Burrows (22/22 episodes)
- Wentworth Miller - Michael Scofield (22/22 episodes)
- Robin Tunney - Veronica Donovan (1/22 episodes)
- Amaury Nolasco - Fernando Sucre (18/22 episodes)
- Marshall Allman - L. J. Burrows (7/22 episodes)
- Wade Williams - Brad Bellick (18/22 episodes)
- Rockmond Dunbar - Benjamin Miles Franklin (19/22 episodes)
- Robert Knepper - Theodore "T-Bag" Bagwell (19/22 episodes)
- Sarah Wayne Callies - Sara Tancredi (20/22 episodes)
- Paul Adelstein - Paul Kellerman (20/22 episodes)
- William Fichtner - Alexander Mahone (22/22 episodes)
- Reggie Lee - William Kim (16/22 episodes)
- Barbara Eve Harris - Felicia Lang (10/22 episodes)
- Matt DeCaro - Roy Geary (7/22 episodes)
- Lane Garrison - David Apolskis (5/22 episodes)
- Leon Russom - Pad Man (5/22 episodes)
- John Heard - Frank Tancredi (5/22 episodes)
- K.K. Dodds - Susan Hollander (4/22 episodes)
- Silas Weir Mitchell - Charles "Haywire" Patoshik (4/22 episodes)
- Peter Stormare - John Abruzzi (3/22 episodes)
- Stacy Keach - Henry Pope (3/22 episodes)
- Patricia Wettig - Caroline Reynolds (3/22 episodes)
The story continues eight hours after the prison escape from Fox River State Penitentiary, focusing mainly on the escapees. The fugitives journey to locations across America with the authorities close behind them as they each pursue their individual goals. Meanwhile, the conspiracy plot develops as "The Company" continues their plan to locate and eliminate Lincoln Burrows and others who get in their way. Much of the storyline concerning the conspiracy concludes by the season finale.
- This is the only season in which T-Bag kills more than 2 characters (discounting Breakout Kings episode, the Bag Man in which he kills 7 characters).
- This season has the most deaths from the Fox River Eight members with 3: first was John Abruzzi, then David "Tweener" Apolskis, followed by Charles Patoshik.
- Only 2 members from the Fox River Eight killed directly this season: Theodore Bagwell and Charles Patoshik.
- This season featured the most deaths from a main character (T-Bag) with the deaths of female characters with 3: Chi Chi, Flora and Denise.