Objective The goal of this study is to investigate the inappropriate activation of Wnt pathway in the hepatocarcinogenesis.Methods We analyzed the alterations of three key components of Wnt pathway, β-catenin, glycogen synthase kinase 3β (GSK-3β) and T cell factor 4 (Tcf-4), in 34 samples of hepatocellular carcinoma (HCC) and paracancerous normal liver by immunohistochemistry, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), direct sequencing, semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization.Results We found 61.8% (21/34) of all the HCCs examined showed an abnormal β-catenin protein accumulation in the cytoplasm or nuclei. RT-PCR-SSCP and direct sequencing showed that β-catenin exon 3 mutations existed in 44.1% (15/34) of the HCCs. No mutations of GSK-3β or Tcf-4 were detected in HCCs. Moreover, mRNA of β-catenin and Tcf-4 but not GSK-3β was found to be over expressed in HCCs. On analyzing the relationship between alterations of β-catenin or Tcf-4 and C-myc or Cyclin D1 expression, we found that the mutations of β-catenin as well as over expression of β-catenin or Tcf-4 gene were independently correlated with C-myc gene over expression in HCCs.Conclusions Our present findings strongly suggest mutations of β-catenin as well as over expression of β-catenin and Tcf-4 gene activate the Wnt pathway in HCC independently with the target gene most likely to be C-myc.