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Abstract: The susceptibility of NC/Nga mice to tumor necrosis factor (TNF)-α was examined by using sensitization with d-galactosamine (d-GalN). Administration of TNF-α and d-GalN killed none of the NC/Nga mice, whereas it killed all of the BALB/c mice. Treatment with TNF-α and d-GalN caused few hepatic lesions in NC/Nga mice but massive hepatocellular apoptosis in BALB/c mice. Unlike BALB/c mice, there was no elevation in caspase 3 and 8 activities in the livers of NC/Nga mice receiving TNF-α and d-GalN. On the other hand, administration of anti-Fas antibody definitely killed both NC/Nga and BALB/c mice via activation of caspases 3 and 8. Treatment with TNF-α and d-GalN led to translocation of nuclear factor (NF)-κB in NC/Nga and BALB/c mice. However, NF-κB translocation was sustained in NC/Nga mice, although it disappeared in BALB/c mice 7 h after the treatment. NF-κB inhibitors activated caspases 3 and 8, and enhanced TNF-α-mediated lethality in NC/Nga. Taken together, the low susceptibility of NC/Nga mice to TNF-α-mediated lethality was suggested to be responsible for the sustained NF-κB activation. [Copyright &y& Elsevier]