Ethanol and aspirin were administered orally to fasted rats and the effects of 16,16-dimethyl prostaglandin E2 (given orally as a pretreatment) were studied using scanning electron microscopy. Gastric secretory studies (pylorus ligation for 2 h) showed that 3 and 30 micrograms/kg of 16,16-dimethyl prostaglandin E2 were nonantisecretory doses and that 100 micrograms/kg was an antisecretory dose. 16,16-Dimethyl prostaglandin E2, given orally at 3-100 micrograms/Kg, induced no appreciable changes in the gastric surface epithelial cells. Oral administration of 1 ml of 50% ethanol invariably induced, within 10 min, extensive exfoliation of surface epithelial cells throughout the corpus and antrum and exposed the lamina propria. 16,16-Dimethyl prostaglandin E2, given orally at 3, 30, and 100 micrograms/kg 30 min before ethanol treatment, had no protective effect. Aspirin, given orally at 30 or 100 mg/kg, also damaged the surface epithelium of both the corpus and the antrum within 10 min. This damage ranged from apical cellular erosions to widespread exposure of the lamina propria. 16,16-Dimethyl prostaglandin E2, given orally at 3 or 30 micrograms/kg 30 min before aspirin treatment, significantly inhibited the gastric damage induced by both 30 and 100 mg/kg of aspirin. The inhibition of damage index was about 50%-60% at either 30 or 100 micrograms/kg of 16,16-dimethyl prostaglandin E2. The mechanism of the protection seen with 16,16-dimethyl prostaglandin E2 remains to be determined.