Tumor necrosis factor (TNF) alpha initiates the activation of a pro-apoptotic pathway involving the recruitment of the death domain containing protein FADD and the subsequent activation of specific proteases (caspases). Many cells are resistant, however, to the cytotoxic effects of TNFalpha due to the concurrent activation of pro-survival pathways involving the transcription factor NFkappaB and TRAF2. Here we show that the TNFalpha-activated FADD/caspase pathway can also exert an unexpected pro-survival effect. Inhibition of this pathway in NIH3T3 fibroblasts or U937 leukemic cells by peptide caspase inhibitors or expression of dominant-negative FADD leads to rapid death following treatment with TNFalpha, whereas control cells are TNFalpha-resistant. FADD/caspase-inhibited cells die by a non-apoptotic mechanism caused by increased production of reactive oxygen species which precedes loss of the mitochondrial membrane potential. Cytotoxicity can be prevented by preincubation with antioxidants including reduced glutathione or by expression of a dominant-negative Rac GTP-binding protein. These results indicate that caspase activation in response to TNFalpha has anti-necrotic as well as pro-apoptotic effects and extend our understanding of the biological role of these proteases.