Fas and tumor necrosis factor receptor 1 (TNFR1) are death receptors involved in various diseases such as hepatitis, sepsis, or graft rejection. Neutralizing antibodies to death ligands or soluble death receptors can inhibit cell death; however, they induce side effects because of their systemic actions. To specifically block death signaling to target cells, we created death domain–deficient (ΔDD) membrane-anchored receptors, delivered to the liver by either recombinant adenovirus or hydrodynamic pressure of nonviral recombinant plasmids. In anti-Fas antibody-induced fulminant hepatitis, mice expressing recombinant Fas-decoy receptors (FasΔDD) in their livers were completely protected against apoptosis and survived fulminant hepatitis. In T-cell–dependent concanavalin A–induced autoimmune hepatitis, FasΔDD antagonist expression prevented hepatocyte damage and mouse death. Finally, TNFR1ΔDD effectively protected mice against LPS-induced septic shock.In conclusion, such ΔDD-decoy receptors act as dominant-negative receptors exerting local inhibition, while avoiding systemic neutralization of apoptosis ligands, and might have therapeutic potential in hepatitis.