Aspirin induces gastric mucosal damage in animals and humans. The purpose of this study was to examine whether cimetidine protects the human gastric mucosa from acute aspirin-induced damage. Eight healthy subjects were studied on 4 separate days. Cimetidine, 400 mg, or placebo was given orally 1 hour before initial endoscopy. The stomach was isolated and atropine given to suppress basal acid secretion. Each study consisted of four 15 min periods during which an acidic test solution was instilled into the stomach. During the second period only, either aspirin (1300 mg, 36 mmol) or control for aspirin (36 mmol HCl) was added to the test solution. Ion fluxes and gastric mucosal potential difference were measured, and endoscopy performed following each test. After placebo, aspirin significantly altered hydrogen ion flux and potential difference versus basal and control. Cimetidine decreased the damaging effect of aspirin. Endoscopic scores increased after aspirin plus placebo, whereas they remained unchanged after aspirin plus cimetidine. Therefore, cimetidine decreased aspirin-induced gastric mucosal damage in humans. As gastric acidity was identical during all studies, the effect of cimetidine was independent of gastric acid secretion.