Of the currently recommended regimens for treatment of uncomplicated gonorrhea, only aqueous penicillin G procaine is effective against infections at all sites. However, procaine penicillin is not effective against penicillinase-producing Neisseria gonorrhoeae and suffers from poor patient acceptability owing to the 10-mL volume of injection and allergic and toxic procaine reactions. Ceftriaxone is a new extended-spectrum cephalosporin with a long serum half-life and is many times more active than penicillin G against both beta-lactamase-positive or -negative strains of N gonorrhoeae. Ceftriaxone was compared as a single, 125-mg, 0.5-mL injection with a single 2-g injection of spectinomycin in difficult to treat pharyngeal gonorrhea in men and women and anorectal gonorrhea of men. Ceftriaxone cured 30/32 (94%) pharyngeal and 52/52 anorectal infections, compared with 6/14 (43%) and 9/9, respectively, for spectinomycin. Both regimens were well tolerated. Ceftriaxone may prove to be a drug of choice for uncomplicated gonorrhea, particularly where homosexual men are treated and/or penicillinase-producing N gonorrhoeae is prevalent.