| Dominic West | Off. James 'Jimmy' McNulty |
| Chris Bauer | Frank Sobotka |
| Paul Ben-Victor | Spiros 'Vondas' Vondopoulos |
| John Doman | Col. William A. Rawls |
| Idris Elba | Russell 'Stringer' Bell |
| Wood Harris | Avon Barksdale |
| Deirdre Lovejoy | Asst. State's Atty. Rhonda Pearlman |
| Clarke Peters | Det. Lester Freamon |
| Wendell Pierce | Det. William 'Bunk' Moreland |
| Lance Reddick | Lt. Cedric Daniels |
| Andre Royo | Reginald 'Bubbles' Cousins |
| Amy Ryan | Off. Beatrice 'Beadie' Russell |
| Sonja Sohn | Det. Shakima 'Kima' Greggs |
| Seth Gilliam | Sgt. Ellis Carver |
| Domenick Lombardozzi | Det. Thomas 'Herc' Hauk |
| Jim True-Frost | Det. Roland 'Prez' Pryzbylewski |
| James Ransone | Chester 'Ziggy' Sobotka |
| Pablo Schreiber | Nick Sobotka |
| Method Man | Melvin 'Cheese' Wagstaff |
| Melanie Nicholls-King | Cheryl |
| Michael Potts | Brother Mouzone |
| Bill Raymond | The Greek |
| Al Brown | Maj. Stanislaus Valchek |
| Robert F. Chew | Joseph 'Proposition Joe' Stewart |
| Kristin Proctor | Aimee |
| Merritt Wever | Prissy |
| Benay Berger | FBI Supervisor Amanda Reese |
| Toni Lewis | F.B.I. Agent |
| Tom Mardirosian | Agent Kristos Koutris |
| Delaney Williams | Sgt. Jay Landsman |
| Teddy Cañez | George 'Double G' Glekas |
| Jeffrey Fugitt | Claude Diggins |
| Lev Gorn | Eton Ben-Eleazer |
| Charley Scalies | Thomas 'Horseface' Pakusa |
| J.D. Williams | Preston 'Bodie' Broadus |
| Chris Ashworth | Sergei 'Serge' Malatov |
| Kevin McKelvey | F.B.I. Agent |
| S. Robert Morgan | Butchie |
| Doug Olear | FBI Spec. Agent Terrance 'Fitz' Fitzhugh |
| William L. Thomas | FBI Special Agent Mason |
| Richard Burton | Sean 'Shamrock' McGinty |
| Luray Cooper | Nathaniel 'Nat' Coxson |
| Jeffrey Pratt Gordon | John 'Johnny Fifty' Spamanto |
| Tommy Hahn | FBI Special Agent Salmond |
| De'Rodd Hearns | Herbert De'Rodd 'Puddin' Johnson |
| Bus Howard | Vernon 'Ott' Motley |
| Wes Johnson | Security Supervisor |
| DeAndre McCullough | Lamar |
| Oleg Prudius | Henchman |
| Donald Rey | Copy Shop Employee |
| Leo Rogstad | Russian Mope |
| Michael Kenneth Williams | Omar Little |