Induction of nuclear factor B (NF-B)-mediated gene expression has been implicated in the pathogenesis of alcoholic liver disease (ALD). Curcumin, a phenolic antioxidant, inhibits the activation of NF-B. We determined whether treatment with curcumin would prevent experimental ALD and elucidated the underlying mechanism. Four groups of rats (6 rats/group) were treated by intragastric infusion for 4 weeks. One group received fish oil plus ethanol (FE); a second group received fish oil plus dextrose (FD). The third and fourth groups received FE or FD supplemented with 75 mg/kg/day of curcumin. Liver samples were analyzed for histopathology, lipid peroxidation, NF-B binding, TNF-, IL-12, monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2), COX-2, iNOS and nitrotyrosine. Rats fed FE developed fatty liver, necrosis and inflammation which was accompanied by activation of NF-B and the induction of cytokines, chemokines, COX-2, iNOS and nitrotyrosine formation. Treatment with curcumin prevented both the pathological and biochemical changes induced by alcohol. Because endotoxin and the Kupffer cell are implicated in the pathogenesis of ALD, we investigated whether curcumin suppressed the stimulatory effects of endotoxin in isolated Kupffer cells. Curcumin blocked endotoxin-mediated activation of NF-B and suppressed the expression of cytokines, chemokines, COX-2 and iNOS in Kupffer cells. Thus curcumin prevents experimental ALD, in part by suppressing induction of NF-B-dependent genes.