Hepatocyte growth factor (HGF) and β‐catenin both play a crucial role in stimulating hepatocyte proliferation, but whether these 2 pathways cooperate in inducing hepatocyte proliferation is unclear. We have previously reported that β‐catenin forms a complex with c‐Met (HGF receptor) that undergoes dissociation because of β‐catenin tyrosine phosphorylation on stimulation by HGF. It is also known that delivery of the human HGF gene cloned in a plasmid under a CMV promoter results in hepatomegaly in mice. In addition, recently characterized β‐catenin transgenic mice also showed hepatomegaly. The present study was based on the hypothesis that HGF‐induced hepatomegaly is mediated, at least in part, by activation of the Wnt/β‐catenin pathway. Here we report that delivery of the human HGF gene delivery in mice led to hepatomegaly via β‐catenin activation in the liver in 1‐ and 4‐week studies. The mechanisms of β‐catenin activation in the 1‐week study included loss of c‐Met–β‐catenin association as well as canonical β‐catenin activation, leading to its nuclear translocation. In the 4‐week study, β‐catenin activation was observed via canonical mechanisms, whereas the c‐Met–β‐catenin complex remained unchanged. In both studies there was an associated increase in the E‐cadherin–β‐catenin association at the membrane. In addition, we generated liver‐specific β‐catenin knockout mice, which demonstrated significantly smaller livers. HGF gene delivery failed to induce hepatomegaly in these β‐catenin conditionally null mice. In conclusion, β‐catenin‐ and HGF‐mediated signaling pathways cooperate in hepatocyte proliferation, which may be crucial in liver development, regeneration following partial hepatectomy, and pathogenesis of hepatocellular carcinoma. (HEPATOLOGY 2006;44:992–1002.)