We compared the safety and efficacies of ofloxacin and trimethoprim-sulfamethoxazole for the treatment of acute uncomplicated cystitis in women enrolled in a multicenter study. Data from three centers were combined for this report because the study design and study populations were identical, and patients were enrolled within an 18-month period. Cure rates for evaluable patients 4 weeks after treatment were high for all regimens: ofloxacin (200 mg) twice daily for 3 days, 22 of 25 (88%) cured; ofloxacin (200 mg) twice daily for 7 days, 42 of 49 (86%) cured; ofloxacin (300 mg) twice daily for 7 days, 25 of 25 (100%) cured; and trimethoprim-sulfamethoxazole (160/800 mg) twice daily for 7 days, 46 of 52 (88%) cured. Ofloxacin was more effective than trimethoprim-sulfamethoxazole in eradicating Escherichia coli from rectal cultures during and 1 week after treatment. Both ofloxacin and trimethoprim-sulfamethoxazole markedly reduced vaginal colonization with E. coli during and 4 weeks after therapy. Emergence of resistant coliforms in rectal flora was found in 5 (19%) of 27 patients treated with trimethoprim-sulfamethoxazole but none of 50 ofloxacin-treated patients who were studied (P = 0.004). Adverse effects were equally common among the four treatment groups. We conclude that 3 to 7 days of ofloxacin is as safe and effective as trimethoprim-sulfamethoxazole for treatment of uncomplicated cystitis in women and that ofloxacin effectively reduces the fecal and vaginal reservoirs of coliforms in such patients.