Neutrophil adherence to the vascular endothelium has been suggested to be a critical event in the pathogenesis of nonsteroidal anti-inflammatory drug (NSAID)-induced gastric damage. Recently, increased plasma levels of tumor necrosis factor-alpha (TNF-alpha), which can increase leukocyte adherence, have been reported after administration of indomethacin. This study was performed to determine the relationship between plasma TNF-alpha levels, leukocyte adherence, and NSAID-induced gastric injury. Administration of indomethacin to rats resulted in a significant elevation of plasma TNF-alpha levels within 30 min and the development of gastric erosions. Pretreatment with dexamethasone and prostaglandin E2 almost completely prevented gastric injury and abolished the rise in plasma TNF-alpha. Pentoxifylline dose dependently reduced both gastric damage and plasma TNF-alpha. Similar effects were observed with three other TNF-alpha synthesis inhibitors and with an anti-TNF-alpha antisera. Pentoxifylline also significantly reduced the extent of antral ulceration induced by naproxen. However, pentoxifylline did not significantly affect indomethacin-induced leukocyte adherence. These results suggest that TNF-alpha plays a critical role in the pathogenesis of NSAID-induced gastric injury, but this cytokine may not be responsible for NSAID-induced leukocyte adherence.