Cirrhotic rats exhibit increased susceptibility to ethanol-induced gastric damage, but the underlying mechanism for this phenomenon remains unclear. Abnormalities of the gastric microcirculation have been reported that may contribute to the increased susceptibility to damage. Decreased gastric synthesis of prostaglandins also likely contributes to impaired mucosal defense in cirrhotic rats. Tumor necrosis factor-alpha (TNF-alpha) has been implicated in mucosal injury, and its synthesis can be inhibited by prostaglandins. Therefore, we hypothesized that TNF-alpha synthesis/ release is altered in cirrhotic rats and plays a role in the pathogenesis of ethanol-induced gastric damage. Cirrhosis was induced by bile duct ligation, whereas controls had sham operations. Topical application of 40% ethanol caused four times as much damage in cirrhotic rats than in controls. Basal plasma TNF-alpha levels did not differ between control and cirrhotic rats, although cirrhotic rats exhibited significantly higher levels of gastric TNF-alpha mRNA. Plasma TNF-alpha increased significantly in control and cirrhotic rats after ethanol administration. Inhibition of TNF-alpha synthesis/release with pentoxifylline, thalidomide, dexamethasone, or immunoneutralization of TNF-alpha (with anti-TNF-alpha) was found to significantly reduce the severity of ethanol-induced gastric mucosal damage in cirrhotic rats. We conclude that TNF-alpha contributes to the pathogenesis of ethanol-induced gastric damage in cirrhotic rats.