Patients with uncomplicated gonorrhea due to .beta.-lactamase-negative Neisseria gonorrhoeae were treated with cefotaxime (1.0 g given i.m. in a single dose) or with aqueous procaine penicillin G (APPG; 4.8 .times. 106 units given i.m.) plus probenecid (1.0 g given orally). Genital or rectal gonococcal infection was cured in 51 (93%) of 55 patients given cefotaxime and in 23 (96%) of 24 patients given APPG plus probenecid. Gonococcal isolates from homosexual men were less susceptible to cefotaxime (geometric mean MIC [minimal inhibitory concentration], 0.021 .mu.g/ml) than were strains isolated from heterosexual men (geometric mean MIC, 0.012 .mu.g/ml; P < 0.05). Genital infection with Chlamydia trachomatis persisted in 4 of 8 patients given cefotaxime and was first detected after treatment in 3 others. Of 23 men with gonococcal urethritis who were treated with cefotaxime and followed for 11-30 days, 10 (43%) developed postgonococcal urethritis; 5 of these were associated with chlamydial infection. Administration of cefotaxime or APPG caused equal pain, but cefotaxime was better tolerated because of the need for only 1 injection. Cefotaxime and APPG plus probenecid are comparable for treatment of uncomplicated genital and rectal infection with .beta.-lactamase-negative N. gonorrhoeae.