Our aim was to compare weekly rufloxacin with daily norfloxacin in the secondary prophylaxis of spontaneous bacterial peritonitis and to examine changes in antibiotic susceptibility in fecal Escherichia coli. The method used was an open randomized clinical trial including 79 patients who received either norfloxacin 400 mg/day or rufloxacin 400 mg/week and followed up for one year. E. coli counts, quinolone susceptibility, and drug concentrations in feces were investigated in 12 patients. Cumulative one-year probability of peritonitis recurrence was 26% for patients on norfloxacin and 36% for those on rufloxacin (P = 0.16). Norfloxacin was more effective in the prevention of peritonitis recurrence due to Enterobacteriaceae (0% vs 22%, P = .01). At the end of follow-up, all 12 patients had E. coli resistant to quinolones in their feces. In conclusion, weekly rufloxacin is not an alternative to daily norfloxacin in the prevention of peritonitis recurrence. The development of quinolone-resistant E. coli in feces may be an important problem in patients on long-term quinolone prophylaxis.