Acute pancreatitis is a common cause of hospitalization and a major source of morbidity worldwide. When it is severe, and especially when it progresses to include necrosis of the pancreas, the risk of infection rises and mortality increases. Early reports suggested prophylactic antibiotics given in severe pancreatitis prevent infection and death. More recent clinical trials do not support this benefit, and meta-analyses on the topic offer conflicting recommendations. In this article, we evaluate the body of published literature examining the use of antibiotics as a preventive measure in acute pancreatitis. The highest quality, currently available data fail to support prophylactic use of antibiotics, which should be added to treatment regimens only where infection has been proven.