A 2-year prospective double-blind study of prophylactic antibiotics in 317 patients undergoing elective total abdominal or vaginal hysterectomy was conducted. Patients randomly received placebo, penicillin, or cefazolin 30 minutes prior to surgery and at 6-hour intervals thereafter for 48 hours. Rigid criteria for postoperative morbidity were established. Vaginal hysterectomy patients given either penicillin or cefazolin prophylaxis had fewer postoperative infections (P < 0.01) compared to those given placebo. A similar trend was noted among women undergoing abdominal hysterectomy; however, this trend was not statistically significant (P > 0.05). Despite continuous surveillance, no change in nosocomial flora or antibiotic sensitivity of bacterial isolates was noted. Adverse drug effects and antibiotic-resistant secondary infections were encountered with similar frequency in all treatment groups.