In this randomized, multicentered study, 157 males and 130 females with laboratory-confirmed, uncomplicated anogenital Neisseria gonorrhoeae infections were evaluated to determine the efficacy and safety of a single 300-mg oral dose of rosoxacin versus 3.5 g of ampicillin plus 1 g of probenecid. A total of 130 males and 101 females were evaluated. Rosoxacin cured 90.3% (P = 0.053) and 94.1% (P = 0.62), respectively, whereas ampicillin was effective in 98.5 and 98% of males and females, respectively. All 39 patients with anorectal infections were cured. One penicillinase-producing N. gonorrhoeae strain was isolated and was eradicated with rosoxacin. Of 212 pretreatment isolates tested, 201 were inhibited by 0.06 micrograms or less of rosoxacin per ml. The MICs of rosoxacin for the remaining 11 isolates ranged up to 0.5 micrograms/ml. The incidence of adverse effects was relatively high (29% for the rosoxacin group versus 18% for the ampicillin group), but none of the reactions required medical intervention nor did they result in serious sequelae.