Abstract: Objective To investigate the Wnt5a expression in obese mice with hepatocellular carcinoma. Methods Two groups of 6-week C57BL/6J mice were fed with chow-diet and high-fat-diet for 8 weeks respectively, to establish obesity model in the latter group. Mice in Hepal-6 group (including normal-body mass mice and obese mice) were injected with Hepa1-6 hepatocarcinoma cell lines through caudal vein, while the controls were given NS. Serum and tissue samples were taken at the age of 18 weeks for serological and morphological study. The expression of Wnt5a and β-catenin in liver were examined by immunohistochemistry. Results At the age of 18-week, tatty degeneration was observed in the livers of obese control mice. Tumor cell masses were found in the livers of both obese and (including normal-body mass mice and obese mice) control mice by inoculation with Hepal-6, while focal necrosis was only observed in the obese+Hepal-6 group. The levels of serum transaminases, cholesterol and alpha-fetoprotein (AFP) were significantly different between groups ( P<0.05). The immunohistochemistry showed that the highest expression of Wnt5a was observed in liver tissues of normal control group, followed in sequence by obese control group, normal+Hepal-6 group, and obese+Hepal-6 group ( P<0.05). The expression of β-catenin was just opposite ( P<0.05). Conclusion The expression of Wnt5a was decreased, and the β-catenin was abnormal accumulation. It may be closely related to the formation and progression of hepatocellular carcinoma.