Nuclear factor κB (NF-κB) is one of the main transcription factors involved in liver regeneration after partial hepatectomy (PH). It is activated upon IκB phosphorylation by the IκB kinase (IKK) complex comprising inhibitor of kappaB kinase 1 (IKK1), inhibitor of kappaB kinase 2 (IKK2), and nuclear factor-B essential modifier (NEMO). We studied the impact of hepatocyte-specific IKK2 deletion during liver regeneration. A 70% PH was performed on IKK2f/f (wild-type) and IKK2ΔLPCmice (hepatocyte-specific IKK2 knockout mice). PH in IKK2ΔLPC compared with IKK2f/f mice resulted in weaker and delayed NF-κB activation in hepatocytes, while nonparenchymal liver cells showed earlier NF-κB activation and higher tumor necrosis factor expression. Additionally, these animals showed increased and earlier serum amyloid A and chemotactic cytokine L-1 levels followed by enhanced polymorphonuclear cell recruitment to the liver. These results correlated with earlier Jun kinase activity, c-myc expression, and matrix metalloproteinase-9 activity, suggesting earlier priming in IKK2ΔLPC mice after PH. These data preceded a more rapid cell cycle progression and earlier hepatocyte proliferation as evidenced through cyclin and 5-bromo-2-deoxyuridine analysis. Interestingly, despite faster G1/S progression, IKK2ΔLPC mice exhibited an enduring mitosis phase, because mitotic bodies were still observed at later stages after PH.Conclusion:We demonstrate that PH in IKK2ΔLPC mice triggers a more rapid and pronounced inflammatory response in nonparenchymal liver cells, which triggers earlier hepatocyte proliferation.