The Wnt/β-catenin pathway plays a vital role in initiating and sustaining hepatocellular carcinoma (HCC). However, few studies have investigated polymorphisms in the Wnt/β-catenin signaling pathway genes in the Chinese Han population. The aim of the present retrospective study was to investigate the correlations between polymorphisms of the Wnt/β-catenin signaling pathway genes (CTNNB1 and WNT2) and HCC susceptibility, development, and progression.Twenty tagging single nucleotide polymorphisms were chosen from HapMap data and genotyped in 320 patients with HCC, 320 chronic hepatitis B virus (HBV)-infected patients without HCC (N-HCC, including 95 liver cirrhosis, 164 chronic hepatitis B, and 61 asymptomatic HBV carriers), and 320 healthy controls. Associations between polymorphisms in the 2 Wnt/β-catenin signaling pathway genes (CTNNB1 and WNT2) and HCC susceptibility, development, and progression were investigated.Genotype AA (P = 0.002, odds ratio [OR] = 2.524) and allele A (P = 0.0003, OR = 1.613) of the WNT2 rs4730775 polymorphism were associated with HCC susceptibility compared with healthy controls. Genotype GA (P = 0.001, OR = 0.567) and allele A (P = 0.002, OR = 0.652) of rs3864004, and genotype AG (P = 0.0004, OR = 0.495) and allele G (P = 0.001, OR = 0.596) of rs11564475 in the CTNNB1 gene were correlated with HCC compared with N-HCC patients. These findings were consistent in dominant and recessive models. Multidimensionality reduction analysis revealed that interactions among rs3864004, rs11564475, and rs4730775 were significantly associated with HCC compared with N-HCC patients. The polymorphism rs4135385 of CTNNB1 genotype GA was associated with a higher risk for Stage III + IV HCC (modified Union for International Cancer Control) (P = 0.001, OR = 2.238).Genetic polymorphisms in the WNT2 and CTNNB1 genes were closely associated with HCC risk and progression in a Chinese Han population.