In the present study, we used TNF-alpha receptor 1 knockout (TNF-alphaR1KO) mice to evaluate a possible role of TNF-alpha on the pathogenesis of ischemia and reperfusion injury of the multivisceral organs. Ischemia and reperfusion injury was induced in mice by clamping the superior mesenteric artery and the celiac artery for 30 min, followed thereafter by reperfusion. Sixty minutes after reperfusion, animals were killed for histological examination and biochemical studies. Injured wild-type (WT) mice developed a significant increase of ileum TNF-alpha levels, myeloperoxidase activity, and marked histological injury and apoptosis. Ischemia and reperfusion injury of the multivisceral organs was also associated with a significant mortality. Reperfused ileum sections from injured WT mice showed positive staining for P-selectin, VCAM, ICAM-1, and E-selectin. The intensity and degree of P-selectin, E-selectin, VCAM, and ICAM-1 were reduced markedly in tissue sections from injured TNF-alphaR1KO mice. Ischemia and reperfusion-injured TNF-alphaR1KO mice also showed a significant reduction of neutrophil infiltration into the intestine, a reduction of apoptosis, an improved histological status of the intestine, and survival. In addition, we investigated the effect of Etanercept, a TNF-alpha soluble receptor construct, on ischemia and reperfusion injury of the multivisceral organs. Etanercept (5 mg/kg administered i.p. 5 min prior to reperfusion) significantly reduced the inflammatory response and the ileum injury. Taken together, our results clearly demonstrate that TNF-alpha plays an important role in the ischemia and reperfusion injury and put forward the hypothesis that modulation of TNF-alpha expression may represent a novel and possible strategy.