The following regimens were randomly administered to 271 men with gonococcal urethritis: 4.8 × 106 units of aqueous procaine penicillin G intramuscularly plus 1 g of probenecid orally (APPG); nine tablets of trimethoprim-sulfamethoxazole (TMP-SMZ; 720 mg of TMP and 3,600 mg of SMZ), orally as a single dose (TMP-SMZ-9); and 12 tablets of TMP-SMZ (960 mg of TMP and 4,800 mg of SMZ) orally as two doses of six tablets taken at a 6-hr interval (TMP-SMZ-12). The failure rates of the APPG, TMP-SMZ-9, and TMP-SMZ-12 regimens were 4%, 23%, and 19%, respectively. APPG was significantly more effective (P < 0.05) than TMP-SMZ-9 or TMP-SMZ-12. Isolates of Neisseria gonorrhoeae from treatment failures as compared to those from treatment successes were significantly more resistant to SMZ (P < 0.01) and to the TMP-SMZ combination in a ratio of 19 parts SMZ to one part TMP (P < 0.05). Minimal inhibitory concentrations of SMZ, TMP, TMP-SMZ, and penicillin G showed positive correlation coefficients.