BACKGROUND/AIMS: We investigated the correlation between toll-like receptor 4 (TLR4) and β-catenin for disclosing the potential pathogenesis of hepatocellular carcinoma (HCC). METHODS: Immunohistochemical toolkit was implemented to measure the expression of TLR4 and β-catenin in 98 cases of HCC tissues and adjacent tissues. After setting up the HepG2.2.15 hepatitis B virus (HBV) related HCC cell line, we divided the cells into the control group, TLR4 siRNA group, β-catenin siRNA group, and pcDNA.3.1 TLR4 + β-catenin siRNA group. Western blot, CCK-8 method, Transwell and flow cytometry were used to detect protein expression, cell proliferation, cell migration and invasion as well as cell apoptosis, respectively. Nude mice tumor model was established to observe the effects of TLR4 and β-catenin on the progression of HBV-related HCC in vivo. RESULTS: The positive rates of TLR4 and β-catenin were higher in HCC tissues compared with normal tissues. Both the TLR4 siRNA group and β-catenin siRNA group exhibited a decreased expression of β-catenin. The proliferation, migration and invasion of tumor cells in the above two groups were suppressed, while the cell apoptosis appeared to be stimulated. As suggested by the results from in vivo and in vitro experiments, the up-regulation of TLR4 could antagonize the corresponding effect of β-catenin siRNA. CONCLUSIONS: TLR4 can affect the expression of β-catenin and hence influence the progression of HBV-related HCC.