TNFα is a pleiotropic cytokine that induces either cell proliferation or cell death. Inhibition of NF-κB activation increases susceptibility to TNFα-induced death, concurrent with sustained JNK activation, an important contributor to the death response. Sustained JNK activation in NF-κB-deficient cells was suggested to depend on reactive oxygen species (ROS), but how ROS affect JNK activation was unclear. We now show that TNFα-induced ROS, whose accumulation is suppressed by mitochondrial superoxide dismutase, cause oxidation and inhibition of JNK-inactivating phosphatases by converting their catalytic cysteine to sulfenic acid. This results in sustained JNK activation, which is required for cytochrome c release and caspase 3 cleavage, as well as necrotic cell death. Treatment of cells or experimental animals with an antioxidant prevents H₂O₂ accumulation, JNK phosphatase oxidation, sustained JNK activity, and both forms of cell death. Antioxidant treatment also prevents TNFα-mediated fulminant liver failure without affecting liver regeneration.