Cefoxitin is a semisynthetic cephamycin with good in vitro activity against Neisseria gonorrhoeae. In a controlled clinical trial, 143 men with uncomplicated gonococcal urethritis received either cefoxitin (2.0 g intramuscularly [im] with 1.0 g of oral probenecid) or aqueous procaine penicillin G (4.8 x 10(6) units im with 1.0 g of oral probenecid). Of the 117 patients who returned for follow-up on days 3-13 after treatment, only 1.8% in the group given cefoxitin and 3.6% in the group given penicillin were not cured. The incidence of pain at the site of injection and rates of adverse reactions were similar for both groups. No hematologic, renal, or hepatic toxicity could be ascribed to either treatment regimen. Although none of the infections were due to beta-lactamase-producing gonococci, the results provide a basis for additional studies of the efficacy of cefoxitin in treatment of infections due to penicillinase-producing N. gonorrhoeae.