Under in vivo microscopic observation, intragastric ethanol instillation has been seen to cause a prompt, marked constriction of submucosal venules, followed by congestion in mucosal capillaries and severe gross mucosal lesion formation. This study was designed to test the hypothesis that the venoconstriction is mediated by leukotrienes and that inhibition of the venoconstriction would protect against ethanol injury. Intragastric application of the leukotriene receptor antagonist MK-571 inhibited both venoconstriction and gross lesion formation. However, although local submucosal application of MK-571 inhibited venoconstriction, it did not protect the overlying gastric mucosa against ethanol injury. We conclude that leukotrienes play a significant pathogenetic role in ethanol-induced gastric mucosal injury, but while the venoconstriction, mediated by leukotrienes, is one of the factors that promote lesion formation, it is not an essential one.