The heterogeneous nature of hepatocellular carcinoma (HCC) and the lack of appropriate biomarkers have hampered patient prognosis and treatment stratification. Using a gene expression profiling approach, we recently identified a novel prognostic HCC subtype that resembles hepatic progenitor cells with the activation of stem cell markers and Wnt–β-catenin signaling, based on EpCAM (epithelial cell adhesion molecule, a hepatic stem cell marker) expression. In this study, we investigated whether the activation of the Wnt–β-catenin pathway regulates EpCAM expression. We found that nuclear accumulation of β-catenin induced, whereas the degradation of β-catenin or inhibition of Tcf/β-catenin complex formation reduced EpCAM gene expression in cultured normal human hepatocytes and HCC cell lines. We identified two Tcf binding elements in the EpCAM promoter that specifically bound to Tcf-4 in an electrophoretic mobility shift assay. EpCAM promoter luciferase activity was down-regulated by the degradation of β-catenin or inhibition of Tcf/β-catenin complex formation. Furthermore, we found that EpCAM-positive HCC is much more sensitive to Tcf/β-catenin binding inhibitors than EpCAM-negative HCC in vitro. Taken together, our data indicate that EpCAM is a Wnt–β-catenin signaling target gene and may be used to facilitate HCC prognosis by enabling effective stratification of patients with predicted pharmacologic responses to Wnt–β-catenin signaling antagonists. [Cancer Res 2007;67(22):10831–9]