Controlled studies have demonstrated that systemic prophylactic antibiotics significantly reduce the sepsis rate after biliary tract surgery. Other studies have documented the efficacy of topical antibiotic irrigation in decreasing the incidence of wound infection after a wide variety of procedures. Whether systemic antibiotics or the combination of systemic and topical antibiotics provide any advantage over topical antibiotics alone, however, has not been determined. Therefore, a prospective, randomized study was carried out comparing topical intra-abdominal and wound antibiotic irrigation (neomycin and polymyxin) with topical antibiotic irrigation plus parenteral antibiotics (gentamicin and penicillin) in 54 patients undergoing "high-risk" biliary surgery. All patients underwent either an elective common bile duct exploration or a biliary-enteric anastomosis for obstructive jaundice. Twenty-five patients were randomized to the group receiving only topical antibiotics, and 29 received topical plus systemic antibiotics. The two groups were similar with respect to age, sex, presence of common duct stones, incidence of jaundice, positive bile cultures at surgery, and type of surgery performed. There were three wound infections in each group, and no patient developed an intra-abdominal abscess. Other infectious complications occurred with similar frequency in the two study groups. This study suggests that topical antibiotics provide effective prophylaxis in biliary tract surgery and that broad-spectrum systemic antibiotic therapy is of no additional benefit. Topical antibiotics provide an alternative means of prophylaxis for patients discovered intraoperatively to be at "high risk" for infection.