Fas is an apoptosis–signaling cell surface antigen that has been shown to trigger cell death upon specific ligand or antibody binding. Treatment of mice with an anti–Fas antibody causes fulminant hepatic failure due to massive apoptosis. To test a putative protective effect of the anti–apoptotic Bcl–2 protein, transgenic mice were generated to express the human bcl–2 gene product in hepatocytes. Early onset of massive hepatic apoptosis leading to death was observed in all nontransgenic mice treated with an anti–Fas antibody. By contrast, hepatic apoptosis was delayed and dramatically reduced in transgenic animals, yielding a 93% survival rate. These results demonstrate that Bcl–2 is able to protect from in vivoFas–mediated cytotoxicity, and could be of significance for preventing fulminant hepatic failure due to viral hepatitis in humans.