Recent anecdotal reports suggest that total parenteral nutrition may be associated with an increased incidence of both acalculous cholecystitis and cholelithiasis. The validity of this association, however, has not been tested in a large population of patients on long-term total parenteral nutrition. Therefore, we assessed the incidence of gallbladder disease among our patients 15 yr and older who had received a minimum of 3 mo of total parenteral nutrition. Of the patients meeting these criteria, 128 were on total parenteral nutrition a mean of 13.5 mo. Nineteen had gallbladder disease before receiving total parenteral nutrition, leaving 109 patients at risk. Of these patients, 25 (23%) developed gallbladder disease after the initiation of total parenteral nutrition. Because of their known propensity for cholelithiasis, 94 of our patients with ileal disorders (Crohn's disease or ileal resection, or both) were considered separately. The 40% incidence of gallbladder disease in these 94 patients was significantly higher than expected from a series of similarly defined patients with ileal disorders not receiving total parenteral nutrition (p less than 0.05). We propose that the enhanced risk of gallbladder disease among patients on long-term total parenteral nutrition results from multiple factors working in concert to promote gallbladder stasis.