A prospective, randomized study was conducted on 219 surgical patients with biliary tract disease. There were 100 patients undergoing elective biliary surgery, and 119 others with suspected biliary sepsis who were assigned to Prophylactic or Therapeutic clinical categories, then randomized into ampicillin or cefamandole treatment groups. Organisms resistant to the antibiotics given were found less often among patients in the cefamandole groups than among those in the ampicillin groups. No postoperative wound or intra-abdominal sepsis (IAS) occurred in the Prophylactic category. In the Therapeutic category there were two cases (3.2%) of wound and IAS in the ampicillin group and one case (1.8%) of wound infection in the cefamandole group. Overall, cefamandole showed superior coverage in vitro against the biliary flora, but both drugs were equally effective in maintaining a low incidence of postoperative sepsis as well as a minimal number of febrile or total hospital days. The authors suggest that the choice of antimicrobials may not be as critical as effective surgical management in the prevention of septic complications following biliary tract surgery.