Intragastric capsaicin protects against ethanol-induced gross mucosal lesion formation by stimulation of afferent nerve endings in the rat stomach. The aims of the present study were to examine histologically the protective effect of capsaicin and to test whether this effect is related to changes in mucosal eicosanoid formation and mucosal blood flow. Intragastric capsaicin (160 μM) significantly reduced gross mucosal lesion formation induced by 25% ethanol. Light microscopy revealed that the depth of erosions was attenuated likewise. However, capsaicin did not prevent ethanol from causing superficial damage to the mucosa as observed by light and scanning electron microscopy. The protective action of capsaicin against ethanol remained unchanged by a dose of indomethacin that reduced the ex vivo formation of prostaglandin E₂ and 6-oxo-prostaglandin F_1α in the gastric mucosa by about 90%. Capsaicin alone did not affect the ex vivo formation of these prostaglandins and of leukotriene C₄. Intragastric capsaicin (160 μM) enhanced gastric mucosal blood flow by 89% as measured by the hydrogen gas clearance technique. This effect was also observed when capsaicin was administered together with 25% ethanol. These data indicate that afferent nerve stimulation by intragastric capsaicin protects against deep mucosal damage in response to ethanol, an effect that seems related to an increase in mucosal blood flow but not to eicosanoid formation.