The study investigates the role of IκB kinase β (IKKβ) in chemically induced liver cancer, a model that does not involve overt inflammation. Surprisingly, mice lacking IKKβ specifically in hepatocytes (Ikkβ−/− mice) exhibited a significant increase in hepatocarcinogenesis caused by diethylnitrosamine (DEN). This was associated with enhanced reactive oxygen species (ROS) production, increased JNK activation, and hepatocyte death, leading 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, preventing excessive DEN-induced carcinogenesis in Ikkβ−/− mice. Additionally, mice lacking IKKβ in both hepatocytes and hematopoietic-derived Kupffer cells showed decreased hepatocarcinogenesis, reduced hepatocyte regeneration, and diminished induction of hepatomotogens. These findings suggest that IKKβ orchestrates inflammatory crosstalk between hepatocytes and Kupffer cells, promoting chemical hepatocarcinogenesis. The results also indicate that anti-inflammatory interventions targeting Kupffer cells may be effective in chemoprevention of HCC.The study investigates the role of IκB kinase β (IKKβ) in chemically induced liver cancer, a model that does not involve overt inflammation. Surprisingly, mice lacking IKKβ specifically in hepatocytes (Ikkβ−/− mice) exhibited a significant increase in hepatocarcinogenesis caused by diethylnitrosamine (DEN). This was associated with enhanced reactive oxygen species (ROS) production, increased JNK activation, and hepatocyte death, leading 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, preventing excessive DEN-induced carcinogenesis in Ikkβ−/− mice. Additionally, mice lacking IKKβ in both hepatocytes and hematopoietic-derived Kupffer cells showed decreased hepatocarcinogenesis, reduced hepatocyte regeneration, and diminished induction of hepatomotogens. These findings suggest that IKKβ orchestrates inflammatory crosstalk between hepatocytes and Kupffer cells, promoting chemical hepatocarcinogenesis. The results also indicate that anti-inflammatory interventions targeting Kupffer cells may be effective in chemoprevention of HCC.