Aprotinin, a Kunitz protease inhibitor, has a wide inhibitory action with particular activity against trypsin, chymotrypsin and kallikrein, making it theoretically attractive in ameliorating the effects of acute pancreatitis. Its use in acute pancreatitis has been studied for the last 50 years with disappointing results. In this paper, we review the previous studies and argue that all the studies have not been adequately powered, have inappropriate end-points, but most importantly have not attained adequate plasma and peritoneal levels of aprotinin to produce sufficient inhibitory activity. We hypothesise that a well-powered study with adequate aprotinin dosing may clarify its clinical benefit in severe acute pancreatitis.