The effect of aspirin on small intestinal function in six healthy volunteers was examined using a segmental perfusion technique, with a test solution of 40 mM D-glucose, 140 mM NaCl, and 0-5% polyethylene glycol. Jejunal glucose, sodium, and water absorption rates were inhibited by 50% after oral administration of 2-6 g aspirin. Adenosine triphosphate (ATP) concentration was assayed in jejunal mucosal biopsies before and after aspirin. There was an almost 50% decrease in mucosal ATP levels after aspirin. This effect may be mediated through cellular injury and impairment of mitochondrial energy metabolism. These data suggest that aspirin may significantly alter small intestinal function. It appears possible that the inhibitory effect of aspirin on glucose absorption may account, at least in part, for the lower blood sugar levels observed with the use of the drug.