&NA;In a prospective, randomized, comparative study, patients undergoing elective major colorectal surgery received four six‐hour doses of either sulbactam (a &bgr;‐lactamase inhibitor) with ampicillin (1 gm with 1 gm), or cefoxitin (2 gm) commencing at induction of anesthesia. The groups were well matched for age, sex, diagnosis, and surgical procedures. Three patients in the sulbactam group (N=44), and four in the cefoxitin group (N=48) developed significant would sepsis. Minor wound sepsis occurred in an additional four sulbactam patients, and in five cefoxitin patients. There was no difference between the groups in deep sepsis or anastomotic leak rates (sulbactam, four patients; cefoxitin, seven patients). No serious side effects were recorded in either group. These results suggest that sulbactam combined with ampicillin provides a safe, effective alternative to cefoxitin for prophylaxis in colorectal surgery.