Single doses of 3.5 g of ampicillin with 1.0 g of probenecid or of 3.0 g of amoxicillin alone were administered orally to 58 males and 56 females with uncomplicated gonococcal infection. The failure rate for genital or anal infection, or both, was 1.7% for ampicillin plus probenecid and 4.2% for amoxicillin alone. However, patients with oropharyngeal infection responded poorly. Seventy-five isolates of Neisseria gonorrhoeae recovered from patients in this study were all inhibited by 1.0 mug or less of ampicillin or amoxicillin per ml; penicillin G, ampicillin, and amoxicillin had similar activity in vitro against these isolates. Serum concentrations of amoxicillin in 10 volunteers remained above the minimal inhibitory concentration for most strains of N. gonorrhoeae for periods up to 10 h after a 3.0-g oral dose. After 2.0 g of ampicillin was given with probenecid, the serum levels during the 5- to 12-h period approached those achieved with 3.5 g of ampicillin plus probenecid, and actually exceeded levels attained during the same interval with 3.0 g of amoxicillin administered alone.