- Dominic Purcell as Lincoln Burrows
- Wentworth Miller as Michael Scofield
- Michael Rapaport as DHS Special Agent Don Self
- Amaury Nolasco as Fernando Sucre
- Wade Williams as Brad Bellick
- Robert Knepper as Theodore "T-Bag" Bagwell
- Chris Vance as James Whistler
- Danay García as Sofia Lugo
- Jodi Lyn O'Keefe as Gretchen Morgan
- Sarah Wayne Callies as Sara Tancredi
- William Fichtner as Alexander Mahone
Recurring characters
- Leon Russom as General Jonathan Krantz
- Shannon Lucio as DHS Special Agent Miriam Hultz
- Stacy Haiduk as Lisa Tabak
- Cress Williams as Wyatt Mathewson
- Kathleen Quinlan as Christina Rose Scofield
- Ted King as Downey
- James Hiroyuki Liao as Roland Glenn
- Michael Bryan French as Gregory White
- Raphael Sbarge as Ralph Becker
- Ron Yuan as Feng Huan
- Barbara Eve Harris as FBI Agent Felicia Lang
- Steve Tom as Stuart Tuxhorn
- Dameon Clarke as Andrew Blauner
- Heather McComb as Rita Morgan
- Graham McTavish as Ferguson
- Jude Ciccolella as Howard Scuderi
- Shaun Duke as Griffin Oren
- Wilbur Fitzgerald as Bruce Bennett
- Michael O'Neill as DHS Director Herb Stanton
- Callie Thorne as Pam Mahone
- Paul Adelstein as Paul Kellerman
- Mark Pellegrino as Patrick Vikan
- Titus Welliver as Scott
- Ivar Brogger as Dr. Vincent Sandinsky
- Jason Davis as FBI Agent Mark Wheeler
- William Mapother as FBI Agent Chris Franco
- Reno Wilson as FBI Agent Wilson Wright
- Rockmond Dunbar as Benjamin Miles "C-Note" Franklin
- John Sanderford as Nathaniel Edison
- Crystal Mantecon as Carmelita
- Marshall Allman as L.J. Burrows
- Kim Coates as Internal Affairs Agent Richard Sullins
- Muse Watson as Charles Westmoreland
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