Several models of tumor necrosis factor (TNF)/TNF-receptor 1 (TNF-R1)-dependent liver injury in mice were investigated with respect to caspase-3–like protease activation representing a pivotal mechanism of apoptotic cell death. Injection of TNF or T-cell–activating agents (i.e., agonistic anti-CD3 antibody or staphylococcal enterotoxin B [SEB]) into galactosamine (GalN)-sensitized mice caused TNF/TNF-R1–dependent liver injury. Intravenous concanavalin A (Con A) alone induced TNF-mediated hepatotoxicity dependent on both TNF-R1 and TNF-R2. Hepatic caspase-3–like proteases were activated in GalN/TNF, GalN/anti-CD3, or GalN/SEB-treated mice, but not in Con A–treated mice. Consistently, the broad-spectrum caspase inhibitor, benzoyloxycarbonyl-val-ala-asp-fluoromethylketone (zVADfmk), prevented TNF-mediated hepatotoxicity in all GalN-dependent models, but failed to protect against Con A. Under transcriptional arrest, however, Con A induced TNF-R1–dependent, but not TNF-R2–dependent, activation of caspase-3–like proteases, and zVADfmk prevented animals from Con A–mediated liver injury under this condition. Histological analysis revealed distinct differences between Con A– and GalN/Con A–induced liver injury regarding apoptotic morphology of hepatocytes. We conclude that impaired transcription induces a switch of Con A hepatotoxicity toward a caspase-3–like protease-dependent pathway. The observation that the functional state of the transcriptional machinery decides whether TNF-driven hepatocyte apoptosis involves activation of caspase-3–like proteases or alternative signaling pathways in vivo might be of relevance for the immunopathology of the liver.