The ideal regimen for the prevention of postoperative infections occurring after elective cholecystectomy has been widely debated. This double-blind, randomized study was conducted to compare the effectiveness and safety of cefuroxime with that of cefazolin in 295 patients undergoing elective cholecystectomy who were considered to be at high risk for postoperative infection. Patients were randomly assigned to receive either a single 1.5 gram dose of cefuroxime plus three doses of placebo, or four 1 gram doses of cefazolin. Each regimen was begun 30 to 60 minutes preoperatively and repeated every six hours for three doses postoperatively. Patients were evaluated during the hospitalization period and again at 30 days. All postoperative infections, including remote infections, were included in the definition of failure. Bacteriologic success rates were 95.5 percent in the cefuroxime group and 98.2 percent in the cefazolin group (p > 0.05). Corresponding clinical success rates were 91.4 and 94.9 percent (p > 0.05), respectively. There was no association between intraoperative bile cultures and the risk of failure or the type of microorganism isolated from postoperative infections. Both regimens were well-tolerated. In view of the additional costs and time associated with preparation and administration of multiple doses, a single preoperative 1.5 gram dose of cefuroxime may be a cost-effective alternative to four 1 gram doses of cefazolin in patients undergoing elective cholecystectomy who are at high risk for postoperative infection.