| 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 |
| Frankie Faison | Acting Commissioner Ervin H. Burrell |
| 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
(credit only) |
| James Ransone | Chester 'Ziggy' Sobotka |
| Pablo Schreiber | Nick Sobotka |
| Melanie Nicholls-King | Cheryl |
| Michael Potts | Brother Mouzone |
| Bill Raymond | The Greek |
| Michael Kenneth Williams | Omar Little
(as Michael K. Williams) |
| Maria Broom | Marla Daniels |
| Al Brown | Maj. Stanislaus Valchek |
| Robert F. Chew | Joseph 'Proposition Joe' Stewart |
| Kristin Proctor | Aimee |
| Tray Chaney | Malik 'Poot' Carr |
| Robert Hogan | Louis Sobotka |
| Michael Salconi | Off. Michael 'Sanny' Santangelo |
| Charley Scalies | Thomas 'Horseface' Pakusa |
| Delaney Williams | Sgt. Jay Landsman |
| Chris Ashworth | Sergei 'Serge' Malatov |
| Richard Burton | Sean 'Shamrock' McGinty |
| Leo Fitzpatrick | Johnny Weeks |
| Jeffrey Fugitt | Claude Diggins |
| S. Robert Morgan | Butchie |
| Luray Cooper | Nathaniel 'Nat' Coxson |
| Kelvin Davis | La La |
| Bus Howard | Vernon 'Ott' Motley |
| Lance Irwin | Maui |
| Jeffrey Pratt Gordon | John 'Johnny Fifty' Spamanto |
| Benay Berger | FBI Supervisor Amanda Reese |
| Tommy Hahn | FBI Special Agent Salmond |
| Kevin McKelvey | F.B.I. Agent
(as Kevin McKelvy) |
| Doug Olear | FBI Spec. Agent Terrance 'Fitz' Fitzhugh |
| William L. Thomas | F.B.I. Agent |
| Isiah Whitlock Jr. | State Sen. R. Clayton 'Clay' Davis |
| Paul D'Elia | Harbor Patrol Cop
(uncredited) |
| Jon Garcia | Ringo
(uncredited) |
| Lev Gorn | Eton Ben-Eleazer
(uncredited) |
| J. Valenteen Gregg | Chess
(uncredited) |
| Christopher Haley | Tech #2
(uncredited) |
| De'Rodd Hearns | Herbert De'Rodd 'Puddin' Johnson
(uncredited) |
| Doug Lory | Big Roy
(uncredited) |
| Paul Majors | Off. MacGaul
(uncredited) |
| DeAndre McCullough | Lamar
(uncredited) |
| Richard Pelzman | Little Big Roy
(uncredited) |
| Oleg Prudius | Henchman
(uncredited) |
| Gary 'D. Reign' Senkus | Frog
(uncredited) |
| Eric Trosman | Dmitri
(uncredited) |
| Schuster Vance | Walt Stokes
(uncredited) |
| Michael Willis | Andy Krawczyk
(uncredited) |
| Brian Anthony Wilson | Det. Vernon Holley
(uncredited) |
| Brook Yeaton | Michael 'White Mike' McArdle
(uncredited) |