We compared the efficacy of orally administered ampicillin, 2 g/d, with that of trimethoprim-sulfamethoxazole, 320 mg/d-1600 mg/d, given for 2 or 6 weeks for outpatient management of acute uncomplicated renal infection in women. Of 98 women participating in the trial, 60 had renal infections with susceptible strains, complied with drug therapy, and completed 6 weeks of follow-up. Before treatment, 39 women had symptoms and signs of acute pyelonephritis; 21 had symptoms of cystitis but positive tests for antibody-coated bacteria. All 60 women had alleviation of symptoms and resolution of bacteriuria after 7 days of therapy. Subsequent recurrences occurred in 12 of 27 women given ampicillin, compared with 4 of 33 given trimethoprim-sulfamethoxazole (p = 0.008). Serotyping showed that most recurrences were reinfections with ampicillin-resistant strains. With each drug, a 2-week regimen of therapy proved as efficacious as a 6-week regimen, but the longer regimen was less well tolerated. We conclude that a 2-week treatment regimen is sufficient to manage acute pyelonephritis in outpatients and that trimethoprim-sulfamethoxazole is preferable to ampicillin therapy.