In a prospective, observational study of antibiotic prophylaxis in gynecologic surgery, the efficacy of pefloxacin in preventing post-operative infections was tested in 178 patients (median age, 47 years) who were hospitalized to undergo abdominal or vaginal gynecologic surgery. Pefloxacin was administered in a single intravenous dose before the surgery in the absence of clinical symptoms, signs, and laboratory data consistent with an infectious etiology. The failure rate of pefloxacin after abdominal surgery was 6.9%, whereas for the vaginal route it was 5.3%. No statistically significant difference was found between the two surgical approaches when the outcome of antibiotic prophylaxis was compared. Failures were related to fever of unknown origin (2 patients), wound infection (3), subfascial abscess (1), and urinary tract infection (1) for abdominal surgery, and to vaginal cuff abscess (1), urinary tract infection (1), pelvic cellulitis (1), and asymptomatic bacteriuria (1) for vaginal surgery. No adverse effects were reported in patients after administration of pefloxacin. None of the patients reported postoperative infections 6 weeks after discharge from the hospital. The use of pefloxacin, a drug with a long half-life and particular efficacy in the urinary tract, appears to be a good choice in a gynecologic surgery because it reduces the incidence of bacteriuria, the principal cause of infectious complications after this type of surgery. These observational results should be confirmed by randomized, masked studies of antibiotic prophylaxis comparing pefloxacin with cephalosporins, semisynthetic penicillins, and other drugs in gynecologic surgery.