IKKβ links chronic inflammation to carcinogenesis by promoting compensatory hepatocyte proliferation that enhances chemical hepatocarcinogenesis. In mice lacking IKKβ in hepatocytes (IkkβΔhep), DEN-induced hepatocarcinogenesis increased, associated with enhanced ROS production, JNK activation, and hepatocyte death, leading to increased compensatory proliferation. However, deletion of IKKβ in both hepatocytes and hematopoietic-derived Kupffer cells reduced carcinogenesis, as Kupffer cells produce hepatomitogens that drive compensatory proliferation. IKKβ orchestrates inflammatory crosstalk between hepatocytes and Kupffer cells, promoting chemical hepatocarcinogenesis. Antioxidant treatment reduced prolonged JNK activation and compensatory proliferation, preventing excessive carcinogenesis. These findings suggest that inflammation and Kupffer cell activity are critical in chemical hepatocarcinogenesis, and targeting Kupffer cells may be a strategy for chemoprevention. IKKβ deficiency in hepatocytes increases susceptibility to DEN-induced hepatocarcinogenesis, likely through ROS accumulation. Loss of IKKβ in Kupffer cells reduces susceptibility, indicating that IKKβ is required for TNFα and IL-6 production in these cells. These results highlight the role of inflammation in hepatocarcinogenesis and suggest that anti-inflammatory strategies targeting Kupffer cells may be effective in preventing HCC.IKKβ links chronic inflammation to carcinogenesis by promoting compensatory hepatocyte proliferation that enhances chemical hepatocarcinogenesis. In mice lacking IKKβ in hepatocytes (IkkβΔhep), DEN-induced hepatocarcinogenesis increased, associated with enhanced ROS production, JNK activation, and hepatocyte death, leading to increased compensatory proliferation. However, deletion of IKKβ in both hepatocytes and hematopoietic-derived Kupffer cells reduced carcinogenesis, as Kupffer cells produce hepatomitogens that drive compensatory proliferation. IKKβ orchestrates inflammatory crosstalk between hepatocytes and Kupffer cells, promoting chemical hepatocarcinogenesis. Antioxidant treatment reduced prolonged JNK activation and compensatory proliferation, preventing excessive carcinogenesis. These findings suggest that inflammation and Kupffer cell activity are critical in chemical hepatocarcinogenesis, and targeting Kupffer cells may be a strategy for chemoprevention. IKKβ deficiency in hepatocytes increases susceptibility to DEN-induced hepatocarcinogenesis, likely through ROS accumulation. Loss of IKKβ in Kupffer cells reduces susceptibility, indicating that IKKβ is required for TNFα and IL-6 production in these cells. These results highlight the role of inflammation in hepatocarcinogenesis and suggest that anti-inflammatory strategies targeting Kupffer cells may be effective in preventing HCC.