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We previously showed that the peroxisome proliferator ciprofibrate increases hepatic NF-κB DNA binding activity in rats, mice, and hepatoma cell lines. Here, we analyzed the response to ciprofibrate in mice that lack the NF-κB p50 gene (p50 -/- ). Wild-type and p50 -/- mice were fed a diet with or without 0.01% ciprofibrate for 10 days. NF-κB DNA binding activity was present and increased after ciprofibrate treatment in wild-type mice, but was not detected in p50 -/- mice. The untreated p50 -/- mice had a higher level of hepatic cell proliferation, as measured by BrdU labeling, than did untreated wild-type mice. However, the increase in proliferation was greater in ciprofibrate-fed wild-type mice than in ciprofibrate-fed p50 -/- mice. The apoptotic index was low in wild-type mice in the presence or absence of ciprofibrate. Apoptosis was increased in untreated p50 -/- mice compared to wild-type mice; apoptosis was reduced in p50 -/- mice after ciprofibrate feeding. The c-Jun and JunB mRNA levels were higher in untreated p50 -/- mice than in untreated control mice; c-Jun mRNA levels increased, whereas JunB mRNA levels decreased in both groups after ciprofibrate treatment. The c-Jun and JunB protein levels were the same in untreated wild-type and p50 -/- mice and increased in both groups after ciprofibrate treatment. Several apoptosis-related mRNAs were higher in untreated p50 -/- mice compared to untreated control mice; expression of these genes increased in both groups after ciprofibrate treatment. These data indicate that NF-κB contributes to the proliferative and apoptotic changes that occur in the liver in response to ciprofibrate.