Oral administration to fasted rats of either absolute ethanol, 0.6 N hydrochloric acid, 0.2 N sodium hydroxide, 25% sodium chloride, or boiling water produced extensive necrosis of the gastric mucosa. Pretreatment with several prostaglandins of the A, E, or F type, either orally or subcutaneously, prevented such necrosis, and the effect was dose-dependent. This property of prostaglandins is called "cytoprotection." The protective effect against oral administration of absolute ethanol was already maximal 1 min after PGE2 given orally, and 15-30 min after PGE2 given subcutaneously. Cytoprotection by prostaglandins is unrelated to the inhibition of gastric acid secretion since, (a) it is maximal at doses that have no effect on gastric secretion, and (b) anti-secretory compounds (cimetidine, methscopolamine bromide) and antacids are not cytoprotective. Although the mechanism of gastric cytoprotection is unknown, prostaglandins appear to increase the resistance of gastric mucosal cells to the necrotizing effect of strong irritants. These results suggest that certain prostaglandins, by a mechanism other than the inhibition of gastric acid secretion, maintain the cellular integrity of the gastric mucosa, and might be beneficial in the treatment of a variety of diseases in which gastric mucosal injury is present.