Nuclear factor kappaB (NF‐κB) plays an important role in the regulation of innate immune responses, apoptosis, inflammation, and oncogenesis. NF‐κB activation in the liver was observed after intrasplenic administration of a lung carcinoma cell line, LLC, which induces liver metastasis. To explore the role of Ikappa B kinase beta (IKKβ), which is the critical kinase of the IKK complex, and NF‐κB activation in metastasis, we injected LLC cells into hepatocyte‐specific IKKβ knockout mice (Ikkβ^Δhep), whole‐liver knockout (Ikkβ^ΔL+H) mice, and control (Ikkβ^F/F) mice. Ikkβ^ΔL+H mice developed liver metastasis with significantly lower liver weights and fewer metastatic foci compared to Ikkβ^Δhep and Ikkβ^F/F mice. Furthermore, intrasplenic LLC injection induced the messenger RNA (mRNA) expression of interleukin (IL)‐6 and IL‐1β in Ikkβ^F/F mice, whereas these genes were less expressed in Ikkβ^ΔL+H mice. IL‐6^−/− mice and treatment with anti‐IL‐6 receptor antibody showed a lesser degree of metastatic tumor, indicating that IL‐6 is associated with liver metastasis. Conclusion: Collectively, these observations suggest that IKKβ/NF‐κB activation controls the development of liver metastasis by way of IL‐6 expression and is a potential target for the development of antimetastatic drugs. (HEPATOLOGY 2009.)