The mucosal protective effect of ebselen was examined in an ethanol-induced rat gastric lesion model. Examination of gastric tissue samples by light microscopy showed that i.g, exposure to 50% ethanol induced gastric injury, which was mon prominent in female rats. Ethanol did not effect the gastric acid secretion examined by means of H+-K(+)ATPase. the increment of which might be harmful in the stomach, But ebselen with or without ethanol kept H+-K(+)ATPase below control levels. Gastric alcohol dehydrogenase (ADH) was mainly responsible for oxidation of ethanol in the stomach before it enters the bloodstream I.g. ethanol exposure inhibited the ADH activity but ebselen eliminated the ethanol-induced inhibition of this enzyme. Therefore, ebselen exhibited a beneficial effect by increasing the gastric ethanol metabolism and by ameliorating the possible tissue toxicity of ethanol. Consistently, we also found that ebselen diminished the blood ethanol level. A gender difference in the blood ethanol levels existed following the same dose of ethanol but then was no difference in ADH activity. Histologically, mucosal injury following ebselen exposure together with ethanol was less severe compared with ethanol treatment alone. We concluded that the decrease in ethanol-induced mucosal injury following ebselen may have contributed to the inhibition of H+-K(+)ATPase and the activation of ADH by ebselen.