D-Galactosamine-sensitized mice challenged with tumor necrosis factor α (TNF) developed severe apoptotic and secondary necrotic liver injury as assessed by histology, measurement of cytosolic DNA fragments and determination of liver-specific enzymes in plasma. Pretreatment of mice with interleukin-1/3 (IL-1) resulted in elevated levels of nitrite/nitrate in serum and rendered mice insensitive towards TNF toxicity. Pharmacological doses of the nitric oxide (NO) donor sodium nitroprusside (SNP) also conferred complete protection against TNF toxicity, suggesting a possible link between IL-1- and NO-induced protection. However, NO-synthesis inhibition by N(G)-monomethyl-L-arginine failed to abrogate IL-1-induced tolerance against TNF toxicity. We conclude that IL-1 and NO protect against TNF-induced liver injury through distinct pathways.