Although an association between gallstones and pancreatitis has been recognized for almost 100 years, the risk of acute pancreatitis in patients with gallstones and the effect of cholecystectomy on this risk have been unknown. The complete medical records of the 2,583 residents of Rochester, Minnesota, who had gallstones diagnosed between 1950 and 1970 were carefully reviewed to detect the development of acute pancreatitis. Acute pancreatitis developed in only 89 subjects (3.4% of the cohort); however, the relative risk for acute pancreatitis (before cholecystectomy) was increased 14 to 35 times in men and 12 to 25 times in women. The overall age- and sex-adjusted incidence of acute pancreatitis of the members of the cohort before cholecystectomy was 6.3 to 14.8 per 1,000 person-years of follow-up. Cholecystectomy in 1,560 patients without a prior attack of pancreatitis reduced the relative risk to 1.9 and 2.0 for men and women respectively. Of 58 patients who had a cholecystectomy after an attack of acute pancreatitis and underwent follow-up for a median of 15 years postoperatively, only 2 had another attack of acute pancreatitis, and the cause of the pancreatitis was unrelated to gallstones in both. In summary, patients with gallstones have a considerably increased relative risk for acute pancreatitis and, regardless of whether prior attacks of pancreatitis have occurred, cholecystectomy reduces this risk to almost the same level as in the general population. Because the overall incidence of pancreatitis is low, however, performance of cholecystectomy to prevent pancreatitis is indicated only if an attack of acute pancreatitis has already occurred.