We have developed an ultrathin endoscope for repeated endoscopy in unsedated subjects and used it with assessment of bleeding rates to investigate aspirin-induced gastric mucosal injury and its prevention by famotidine. Compared with placebo, 900 mg of aspirin b.i.d. taken for 48 h caused significant endoscopic injury (median grade 3.5, interquartile range 2-4, modified Lanza scale, p less than 0.01), with an increase in mucosal bleeding from 2.0 (geometric mean; 95% confidence limits, 1.1-3.9) microliters/12 min, to 8.3 (2.4-28.8) microliters/12 min (p less than 0.05). Famotidine (20 mg b.i.d.) raised intragastric pH and reduced endoscopic antral injury (median 1.5, interquartile range 0.5-2, p less than 0.05) and bleeding [3.1 (1.2-8.3) microliters/12 min, p less than 0.01] to levels not significantly different from placebo [1 (0-1) and 2.0 (1.1-3.9) microliters/12 min, respectively]. By contrast, 2 mg of famotidine b.i.d. had no significant effect on intragastric pH endoscopic injury or bleeding rates. The two assessments of gastric mucosal injury correlated strongly (r = 0.71, p less than 0.01). The reduction in bleeding with famotidine tended to be higher, the greater the intragastric pH (r = 0.66, p = 0.057). Ultrathin endoscopy is a simple technique that validates gastric mucosal bleeding as a measure of acute gastric mucosal injury in humans. Acid suppression is an effective method of ameliorating this injury.