The effect of acetylsalicylic acid (aspirin) on the ultrastructure of the 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 desquamation. 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 secondary lysosomes, probably representing autophagolysosomes. The simultaneous increase of multi vesicular 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 during absorption cause cellular injury that can usually be restored by cellular repair mechanisms but that high drug concentrations may lead to irreversible cell damage.