Hypothesis: Cephalosporins are widely used and considered to be effective as prophylaxis in biliary surgery. Nevertheless, they lack activity against enterococci. We conducted a study to compare the efficacy of ampicillinsulbactam vs cefuroxime in preventing surgical site infections following elective cholecystectomy. Design: A prospective randomized controlled trial. Setting: A major tertiary care hospital. Patients: Four hundred eighteen randomized patients (of 549 total), who from July 2002 to August 2004 underwent elective open or laparoscopic cholecystectomy with prospective assessment for development of surgical site infections for 1 month postoperatively. Intervention: A single intravenous dose of 1.5 g of cefuroxime (group A, n = 207) or 3 g of ampicillinsulbactam (group B, n = 211) was administered during induction of anesthesia. Bile and gallbladder mucosal cultures were taken intraoperatively from all patients. Main Outcome Measure: Number of postoperative surgical site infections. Results: A postoperative surgical site infection was noted in 19 (4.5%) of 418 patients, 18 from group A and 1 from group B (PϽ.001). In the group that received cefuroxime, 15 (83.3%) of 18 surgical site infections were due to Enterococcus species. Intraoperative bactibilia as well as intraoperative gallbladder rupture were associated with surgical site infections (PϽ.001). Conclusions: A single dose of ampicillin-sulbactam favored better compared with cefuroxime for prevention of postoperative surgical site infections due to Enterococcus species after elective cholecystectomy. Ampicillinsulbactam may be a better agent for antimicrobial prophylaxis in high-risk patients undergoing elective cholecystectomy, especially in a setting where the incidence of enterococcal infections is higher.