A total of 120 men with uncomplicated infections caused by beta-lactamase-negative, highly penicillin-susceptible strains of Neisseria gonorrhoeae were included in this study. They were randomly assigned to regimens of either piperacillin (2.0 g) or procaine penicillin G (4.8 X 10(6) U) intramuscularly, both delivered concomitantly with an oral dose of 1.0 g probenecid. A total of 103 patients completed the study, providing data from 112 infected sites: for the penicillin regimen--urethra, 46; pharynx, 5; and rectum, 4; for the piperacillin regimen--urethra, 53; pharynx, 3; and rectum, 1. In the penicillin group, there were no failures at any of the infected sites. In the piperacillin group, all except one pharyngeal infection were cured. Also, in the piperacillin group, four men visit, whereas no cases of this type occurred in the penicillin group. No major side effects were noted in either group. Clinically, piperacillin was as effective as procaine penicillin G in the treatment of gonococcal urethritis in men. Pharyngeal infection may be refractory to piperacillin therapy.