The development of hepatocellular carcinomas (HCC) appears to be a multistep process that takes several decades in humans. However, the identities of specific gene alterations and their contribution to HCC pathogenesis remain poorly understood. We previously reported that Lkb1+/- mice spontaneously develop multiple hepatic nodular foci (NdFc) followed by HCC, and that the conditional activation of beta-catenin in Catnblox(ex3) mouse livers alone does not cause tumor formation. We show here that the conditional activation of beta-catenin accelerates HCC development in Catnb+/lox(ex3)Lkb1+/- compound mutant mice, affecting displastic hepatocytes in NdFc that suffered LOH at the Lkb1 locus. We further show that beta-catnin activation provides HCC with a growth advantage as well as transplantability. These results suggest that the loss of Lkb1 contributes to the formation of dysplastic NdFc, and that Wnt signaling activation is involved in ensuing progression toward HCC. A combination of these sequential changes can be a practical model for a subset of human HCC. (Cancer Sci 2009).