Surgical site infection is a common complication following pancreaticoduodenectomy and is a major source of postoperative morbidity. Surgical site infection is more common among patients who undergo preoperative biliary instrumentation, likely because of the introduction of intestinal flora into the normally sterile biliary tree. Frequently, bacterial isolates from surgical site infections after pancreaticoduodenectomy demonstrate resistance to the antibiotic agents typically used for surgical prophylaxis, suggesting that broad-spectrum coverage may be beneficial. This chapter summarizes the current evidence regarding surgical site infection following pancreatic surgery and describes the rationale and methodology underlying a multicenter randomized trial evaluating piperacillin-tazobactam compared with cefoxitin for surgical site infection prevention following pancreaticoduodenectomy. As the first U.S. randomized surgical trial to utilize a clinical registry for data collection, this study serves as proof of concept for registry-based clinical trials. The trial has successfully completed patient accrual, and study results are forthcoming.