| Dominic West | | Det. James 'Jimmy' McNulty |
| John Doman | | Dep. Comm. for Operations William A. Rawls |
| Deirdre Lovejoy | | Asst. State's Atty. Rhonda Pearlman |
| Wendell Pierce | | Det. William 'Bunk' Moreland |
| Lance Reddick | | Lt. Cedric Daniels |
| Sonja Sohn | | Det. Shakima 'Kima' Greggs |
| Seth Gilliam | | Sgt. Ellis Carver |
| Domenick Lombardozzi | | Det. Thomas 'Herc' Hauk |
| Clarke Peters | | Det. Lester Freamon |
| Andre Royo | | Reginald 'Bubbles' Cousins |
| Michael Kenneth Williams | | Omar Little 50 episodes, 2002-2008 |
| Jim True-Frost | | Det. Roland 'Prez' Pryzbylewski |
| Frankie Faison | | Acting Commissioner Ervin H. Burrell |
| Corey Parker Robinson | | Detective Leander Sydnor |
| Delaney Williams | | Sergeant Jay Landsman |
| J.D. Williams | | Preston 'Bodie' Broadus |
| Wood Harris | | Avon Barksdale |
| Idris Elba | | Russell 'Stringer' Bell |
| Aidan Gillen | | Councilman Thom |
| Jamie Hector | | Marlo Stanfield |
| Gbenga Akinnagbe | | Chris Partlow |
| Robert Wisdom | | Howard 'Bunny' Colvin |
| Anwan Glover | | Slim Charles |
| Felicia Pearson | | Felicia 'Snoop' Pearson |
| Chad L. Coleman | | Dennis 'Cutty' Wise |
| Tray Chaney | | Malik 'Poot' Carr |
| Michael Kostroff | | Maurice 'Maury' Levy |
| Isiah Whitlock Jr. | | State Senator R. Clayton 'Clay' Davis |
| Robert F. Chew | | Joseph 'Proposition Joe' Stewart |
| Michael Salconi | | Officer Michael 'Sanny' Santangelo |
| Reg E. Cathey | | Norman Wilson |
| Jermaine Crawford | | Duquan 'Dukie' Weems |
| Tristan Mack Wilds | | Michael Lee |
| Glynn Turman | | Mayor Clarence V. Royce |
| Edward T. Norris | | Det. Edward Norris |
| Amy Ryan | | Off. Beatrice 'Beadie' Russell |
| Al Brown | | Maj. Stanislaus Valchek |
| Richard Burton | | Sean 'Shamrock' McGinty |
| Benjamin Busch | | Off. Anthony Colicchio |
| Ryan Sands | | Off. Lloyd 'Truck' Garrick |