&NA;A controlled, prospective, randomized study of 457 patients undergoing colonic surgery was done to compare systemic cefamandole therapy to neomycin‐erythromycin in reducing postoperative septic complications. Parenteral cefamandole and cephalothin were given before, during, and after surgery to achieve maximal antimicrobial coverage in the blood, tissues, peritoneum, and urine. Such protection is not obtained with oral antibiotic preparation. Major surgical indications were carcinoma in 216 patients and diverticulitis in 107 patients. More than half the patients had colonic perforations, obstruction, or fistulas. All patients were operated upon by a single surgeon during 1975‐1980. Cephalothin (151 patients), combined with neomycin‐erythromycin, resulted in an 11.3 per cent rate of post‐operative septic complications. Cefamandole treatment in 112 patients resulted in an 8.9 per cent postoperative infection rate compared with 16.3 per cent in 141 matched control patients.