<b><i>Objectives:</i></b> Mutation of the exon 3 of <i>CTNNB1</i>, the coding gene of β-catenin, is a crucial molecular mechanism leading to aberrant activation of the Wnt/β-catenin pathway, which is highly associated with the carcinogenesis of hepatocellular carcinoma (HCC). The prevalence and clinical significance of <i>CTNNB1</i> mutations in advanced HCC remain unclear. <b><i>Methods:</i></b> Patients with advanced HCC and available pathologic tissues (either obtained when diagnosed at advanced or early stages) were enrolled in this study. Direct sequencing of exon 3 of <i>CTNNB1</i> was performed to detect somatic mutations. The associations between <i>CTNNB1</i> mutations and clinicopathologic features were analyzed. <b><i>Results:</i></b> A total of 115 patients were enrolled, among whom 78 (67.8%) had chronic hepatitis B virus infection. Twenty-one (18.3%) patients were found to have <i>CTNNB1</i> mutations, all of which were missense mutations. The <i>CTNNB1</i> mutation rates were similar among pathologic tissues obtained at advanced and early stages (17.5 and 20.0%, respectively). Patients aged over 60 years were more likely to have <i>CTNNB1</i> mutations than patients younger than 60 years (32.6 vs. 8.7%, p = 0.001). The mutations were not associated with survival or other clinicopathologic features. <b><i>Conclusion:</i></b> In patients with advanced HCC, <i>CTNNB1</i> mutations were not prognostically significant. No apparent increase of <i>CTNNB1</i> mutations occurred during the progression of HCC.