Aspirin breaks the gastric mucosal barrier. We studied the effect of aspirin on this barrier, correlating changes in potential difference and ultrastructure. Mean control potential difference for seven subjects was -48 +/- 1.0 mV. Oral aspirin, 600 mg in 100 ml of saline, reduced potential difference to -39 +/- 1.4 mV (P less than 0.001) within 10 minutes. Gastric biopsies were taken during control, aspirin- instillation, and recovery periods. Damage was present in all biopsies after aspirin. Light microscopy showed focal cell disruption, loss of mucous granules, and apical membrane rupture. Transmission electron microscopy showed intact tight junctions. Scanning electron microscopy showed loss of normal cobblestone cell apices, giving a honeycombed surface. Ten minutes after aspirin, 25% of surface epithelial cells were damaged. Marked recovery was noted at 1 hr, with a normal potential difference and only 9% cell damage. We conclude that single "routine" doses of aspirin cause focal damage to normal human gastric mucosa.