The purpose of this study was to determine the incidence of death as the initial manifestation of cholelithiasis. Records of patients who died or underwent cholecystectomy for gallstone-related disease at Duke University Medical Center between 1976 and 1985 were reviewed. Thirty patients died, six of whom (20%) had previous episodes of biliary pain and stone documentation. Twenty-four (80%) were asymptomatic (three with previous incidental diagnosis of cholelithiasis). Reason for admission included acute cholecystitis (nine), pancreatitis (eight), biliary pain (six), cholangitis (four), jaundice (one), and endocarditis (one). Three patients died of gallstone complications without surgical intervention; one patient had renal failure and two had septicemia. Other causes of death were: sepsis (seven patients), cardiac failure (six), pulmonary complications (four), renal failure (three), cerebrovascular accident (three), liver failure (two), pancreatitis (one), and gastrointestinal bleeding (one). During this period, 1731 cholecystectomies were performed without mortality. In this group, the patients were younger (50 +/- 8 years vs. 64 +/- 13 years, p less than 0.001), and had a lower incidence of cirrhosis (p less than 0.001) and diabetes (p less than 0.002). The sex ratio was inverted (p less than 0.001). This study demonstrates that death from gallstones is uncommon (three cases per year), as is death from their initial clinical manifestation (1.2%). The risk of death is two- and ninefold higher in patients with acute cholecystitis or acute pancreatitis. Age, cirrhosis, and diabetes are important determinants of outcome.