We studied whether sucralfate's protection of the gastric mucosa against ethanol induced injury in the rat is prostaglandin mediated. Rats received intragastric pretreatment: i) saline, ii) sucralfate, and iii) indomethacin-sucralfate. One hour later gastric contents were obtained for measurements of prostaglandin E2 and 2 ml of 100% ethanol were instilled. Rats were sacrificed 1 h later. The gastric mucosa was assessed: a) macroscopically by planimetry, b) by quantitative histology, and c) by measurements of gastric volume, pH and sodium. We found that sucralfate significantly increased gastric luminal release of prostaglandin E2. The increase was completely abolished by indomethacin pretreatment. Sucralfate protected the gastric mucosa against ethanol injury reducing macroscopic and histologic necrosis. Indomethacin (prostaglandin synthetase inhibitor) given 2 h prior to sucralfate markedly abolished its protective action against ethanol induced necrosis by 70%. These findings indicate that prostaglandins mediate some of the protective action of sucralfate. Sucralfate appears to have additional protective action which is prostaglandin independent.