The canine gastric mucosa has a uniquely hydrophobic or nonwettable surface that is rapidly disrupted by damaging agents such as aspirin. In this study we investigated the effects of acidified aspirin on the wettability of the luminal surface of gastric mucosae mounted in Ussing chambers in the presence of varying concentrations of 16,16-dimethyl prostaglandin E2. It was determined that surface hydrophobicity of the stomach, as measured by contact angle measurements, could be reduced by 50% with an aspirin concentration of 5 mM in the mucosal bath and that this change could be completely and significantly reversed by the addition of 16,16-dimethyl prostaglandin E2 (1 microgram/ml) to the nutrient compartment. 16,16-Dimethyl prostaglandin E2 at this dose was less effective in restoring the surface hydrophobicity in response to a higher concentration of aspirin (20 mM) that abolished the nonwettable property of the tissue. The reduced surface hydrophobicity in the presence of 5 mM aspirin could be increased in a dose response relationship to the nutrient 16,16-dimethyl prostaglandin E2 concentration, with an effect being seen at doses as low as 1 ng/ml. These results support the concept that prostaglandins may protect the stomach by the maintenance of a nonwettable hydrophobic lining between damaging agents in the lumen and the gastric epithelium.