BACKGROUND &AIMS:: Apoptosis of hepatocytes is a METHODS:: Involvement of tumor necrosis factor (TNF)-a and Fas signaling was evaluated using various knockout mice (TNF-receptor-1 [TNF-Rl]-/-, Fas[Ipr]-/-, and Fas ligand[gld]-/-) and wild-type mice pretreated with pentoxifylline, an inhibitor of TNF-α synthesis. METHODS:: Expression of TNF-α was increased after ischemia and reperfusion in wild-type mice and TNF-Rl-deficient mice when compared with sham-operated animals. Pentoxifylline prevented up-regulation of TNF-α expression. Inhibition of TNF-α resulted in significant decrease of serum aspartate aminotransferase levels and prolonged animal survival. Markers of apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nickend labeling staining, cytochrome C release, and caspase 3 activity) were consistently decreased, and animal survival was prolonged after blocking TNF-α. In contrast, inhibition of Fas signaling did not alter parameters of tissue injury or apoptosis, and animal survival remained unchanged. CONCLUSIONS:: We identify TNF-a as a crucial inducer of apoptotic cell death in the ischemic liver. A role for Fas could not be identified. These findings may lead to novel strategies to prevent ischemic injury of the liver.