The effect of acetylsalicylic acid (aspirin) on the ultrastructure of gastric and jejunal mucosa was investigated in patients undergoing gastric surgery and in guinea pigs. The drug caused various degrees of damage to the surface mucous cells in both species perceptible as general signs of cytolysis in situ or as desquanmation. In patients pretreated with aspirin, an increase of secondary lysosomes was noted in the gastric parietal cells but not in the animals. In the intestinal epithelial cells of both species there was a marked increase of multivesicular bodies and the occurrence of transitional stages between the two organoids suggest a functional interrelationship. Since no specific alteration of any cellular organoid was detected, the drug-induced injury is assumed to occur on a molecular level in the cytoplasm. It is concluded that the intracellular concentrations of aspirin in gastrointestinal mucosal cells mechanims but that high drug concentrations may lead to irreversible cell damage.