OBJECTIVE We compared the efficacy and safety of once-daily fleroxacin and twice-daily ciprofloxacin in patients with complicated urinary tract infections. METHODS Using a prospective, open, randomized, multicenter study design, 133 patients (67 fleroxacin, 66 ciprofloxacin) were treated with doses of either 200 mg. of fleroxacin once daily or 250 mg. of ciprofloxacin twice daily in phase 1. In phase 2, 211 patients (103 fleroxacin, 108 ciprofloxacin) received 400 mg. of fleroxacin once daily or 500 mg. of ciprofloxacin twice a day. RESULTS In phase 1, bacteriological efficacy was excellent only against sensitive pathogens, such as Escherichia coli (84% with fleroxacin, 88% with ciprofloxacin), but high failure rates were observed in infections caused by Pseudomonas species (56% with fleroxacin, 67% with ciprofloxacin) and gram-positive organisms (52% with fleroxacin, 67% with ciprofloxacin). In phase 2, bacteriological overall success rate was 88% in the fleroxacin group and 84% in the ciprofloxacin group. Clinical overall success was observed in more than 90% of patients in both groups (94% with fleroxacin, 93% with ciprofloxacin). No statistically significant differences between the drugs were observed in efficacy during phase 2, including a 4 to-6-week followup. Tolerance was also similar for fleroxacin and ciprofloxacin, with about 20% of patients reporting adverse events. CONCLUSIONS The results suggest that both fleroxacin and ciprofloxacin are safe and effective for the treatment of complicated urinary tract infections at the higher doses used in phase 2, with fleroxacin offering the advantage of a once-daily dosing regimen. Lower doses of fleroxacin (200 mg. once daily) should only be used to treat urinary tract infections caused by gram-negative organisms with minimum inhibiting concentrations of less than 0.5 mg./l.