IκB kinase β (IKKβ), required for NF-κB activation, links chronic inflammation with carcinogenesis. We investigated whether IKKβ is involved in chemically induced liver cancer, a model not involving overt inflammation. Surprisingly, mice lacking IKKβ only in hepatocytes (Ikkβ^Δhep mice) exhibited a marked increase in hepatocarcinogenesis caused by diethylnitrosamine (DEN). This correlated with enhanced reactive oxygen species (ROS) production, increased JNK activation, and hepatocyte death, giving rise to augmented compensatory proliferation of surviving hepatocytes. Brief oral administration of an antioxidant around the time of DEN exposure blocked prolonged JNK activation and compensatory proliferation and prevented excessive DEN-induced carcinogenesis in Ikkβ^Δhep mice. Decreased hepatocarcinogenesis was also found in mice lacking IKKβ in both hepatocytes and hematopoietic-derived Kupffer cells. These mice exhibited reduced hepatocyte regeneration and diminished induction of hepatomitogens, which were unaltered in Ikkβ^Δhep mice. IKKβ, therefore, orchestrates inflammatory crosstalk between hepatocytes and hematopoietic-derived cells that promotes chemical hepatocarcinogenesis.