- Eric: an actor and waiter. Eric's prone to occasional bouts of flighty behavior.
- Joey: a police officer, and the more down-to-earth of the couple.
The strip also features a sizable supporting cast, including: Eric and Joey's neighbors Sue and Simone, a lesbian couple; Andy, Eric's younger brother; David, a hairstylist friend; Omar and Ted, the bartenders at Eric and Joey's favorite bar; and more.
A Couple of Guys contains examples of:
- Big Applesauce: The strip's set in New York City.
- Bi the Way: Eric's brother Andy is bi.
- Cast Full of Gay
- Comic-Book Time: Mostly averted. The characters have aged roughly in real time since the strip's debut. April, Eric's niece, has gone from being a newborn infant to her teens, while David's pet dog Matisse passed away from old age.
- Flyover Country: Eric's originally from Ohio, where his occasionally seen parents still live. Eric and Joey also take annual vacations to Chicago for the International Mister Leather conference.
- Good Angel, Bad Angel: Angel and Devil, serving as Eric's conscience, are occasionally seen. The two eventually became a couple.
- New York City Cops: Joey.
- Nobody Over 50 Is Gay: Averted; there's a few older gay characters seen. These include one of Eric and Joey's neighbors, plus a few of the patrons at Omar and Ted's bar.