A total of 63 adult patients with uncomplicated acute pyelonephritis were enrolled in a multicenter, randomized comparison of lomefloxacin (400 mg orally once daily for 14 days) and trimethoprim/sulfamethoxazole (TMP/SMX, 160/800 mg orally twice daily for 14 days). Study participants were predominantly female (70% in the lomefloxacin group and 80% in the TMP/SMX group). Escherichia coli was isolated from pretreatment urine cultures in 87.5% of the lomefloxacin group and 80.0% of the TMP/SMX group. Baseline pathogens were eradicated in 100% of evaluable patients in the lomefloxacin group 5-9 days after the end of therapy and in 88.9% of patients in the TMP/SMX group (p = 0.05). The clinical cure rate 5-9 days after therapy with lomefloxacin was 65.0% and for TMP/SMX was 68.4%. At the 4-6 week follow-up in the lomefloxacin group, nine pathogens remained eradicated, one E. coli was isolated, and the results for 14 pathogens were unknown or unevaluable. In the TMP/SMX group, 12 pathogens remained eradicated, three E. coli and one Group D Streptococcus were isolated, and the results for nine pathogens were unknown or unevaluable. Both treatment regimens were well tolerated; adverse events occurred in 12% of patients in the lomefloxacin group and in 17% in the TMP/SMX group. Events considered by the investigators to be probably related to treatment occurred in three patients in each group. In conclusion, once-daily lomefloxacin (400 mg) was a well tolerated and effective alternative to twice-daily TMP/SMX (160/800 mg) for the treatment of adults with uncomplicated acute pyelonephritis.