This study enrolled patients with complicated urinary tract infections (UTIs) in a trial to determine the efficacy and safety of sequential therapy with intravenous fleroxacin (first 3 days) followed by oral fleroxacin, for a total course of 7-14 days, both administered at a dosage of 400 mg once a day. We enrolled 68 patients with complicated UTIs or acute pyelonephritis, 32 of whom were evaluable for bacteriologic and clinical efficacy. The pathogens isolated included Escherichia coli, 15; enterococci, 9; miscellaneous, 15. Intravenous fleroxacin was given for a mean of 3.2 days, followed by oral fleroxacin for a mean of 5.3 days. A total of 27 patients were clinically cured (84%), two improved, and three failed. A total of 26 patients were bacteriologically cured (81%), and six failed (19%). The bacteria that were not eradicated included enterococci, 4; Staphylococcus epidermidis, 1; and Pseudomonas species, 1. One enterococcal isolate became resistant to fleroxacin. Four patients were bacteremic (E. coli, 3; Proteus mirabilis, 1); the pathogen was eradicated in all cases. Two patients developed urinary enterococcal superinfections. A total of 12 patients experienced 16 adverse reactions remotely, possibly, or probably related to fleroxacin (insomnia, 3; dizziness, 2; miscellaneous, 11). One patient had a grand mal seizure after aspirating gastric contents; the seizure was thought to be only remotely related to the study drug. Fleroxacin was discontinued in two patients because of adverse effects (phlebitis at intravenous access site, 1; anxiety and insomnia, 1). Only minor and asymptomatic laboratory abnormalities were observed. All clinical and laboratory abnormalities resolved with discontinuation of the study drug. Fleroxacin is a safe and effective antibiotic for sequential intravenous and oral treatment of acute pyelonephritis and complicated UTIs. Enterococci may be problematic pathogens, as reported with other fluoroquinolones.