The effect of food intake and gut bacterial flora on gastrointestinal lesions caused by oral indometacin (IND) was studied in rats. A dose of 10 mg/kg IND caused no intestinal lesions when the animals were starved before and after treatment; it produced moderate lesions when the animals were continuously fed and maximal lesions when the animals were fed in the postdrug period after starvation in the predrug period. Under germ-free conditions, 15 mg/kg IND induced significantly less intestinal lesions than under specific pathogen-free conditions. The differences in the magnitude of intestinal lesions under the varying feeding and maintenance conditions were not associated with different IND concentrations in the jejunal mucosa. The dose of 10 mg/kg IND produced most gastric lesions when the animals were previously starved for 24 h and subsequently fed, medium lesions in continuously starved animals and only a few lesions in animals fed before and after IND. The disposition of IND from the gastric mucosa did not differ under the different feeding conditions. As the dose of IND is high enough to inhibit prostaglandin synthesis, it was concluded that additional factors are important for the development of gastrointestinal lesions caused by IND. Secondary bile acids in conjunction with IND are important for the development of intestinal lesions, while gastric acid influences the intensity of gastric lesions.