NF-κB regulates liver cell death during development, regeneration, and neoplastic transformation. For example, we showed that oncogenic Ras- or Raf-mediated transformation of rat liver epithelial cells (RLEs) led to altered NF-κB regulation through IKK complex activation, which rendered these cells more resistant to TGF-β1-induced apoptosis. Thus, based on these findings, we sought to determine whether NF-κB could also be involved in tumor growth of liver cells in vivo. Hepatocellular carcinomas (HCCs) derived from bitransgenic mice harboring TGF-α and c-myc transgenes targeted specifically to the liver were compared with HCCs from c-myc single transgenic mice. Tumors from bitransgenic mice are characterized by a higher frequency of appearance, lower apoptotic index, and a higher rate of cell proliferation. Here we show that NF-κB is activated in HCCs of double TGF-α/c-myc transgenic mice, but not of c-myc single transgenic mice, suggesting that TGF-α mediates induction of NF-κB. Activation of the IKK complex was observed in the HCCs of double TGF-α/c-myc transgenic mice, implicating this pathway in NF-κB induction. Lastly, activation of the Akt/protein kinase B (PKB), which has recently been implicated in NF-κB activation by PDGF, TNF-α, and Ras, was also observed. Importantly, human HCC cell lines similarly displayed NF-κB activation. Thus, these studies elucidate an anti-apoptotic mechanism by a TGF-α-Akt/PKB-IKK pathway, which likely contributes to survival and proliferation, thereby accelerating c-myc-induced liver neoplastic development in vivo.