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Objective To investigate the influence and the possible molecular mechanisms of oxymatrine (OM) on the proliferation, invasion, and metastasis of hepatocellular carcinoma. Methods Human hepatoma cell line HepG2 was randomly divided into the negative control group, low-dose, medium-dose, and high-dose OM groups. The negative control group was added with the cell culture fluid, besides,the OM groups were added with 1.0, 2.0, and 4.0 mg/mL OM and cell culture fluid. The cell proliferation was measured by MTT method and the inhibition rate of cell proliferation was calculated. The invasion and migration of cells in each group were detected by Transwell chamber assay. The expression of E-cadherin and CD44 mRNA in the OM groups was detected by real-time PGR, and Western blotting was used to detect the protein expression of E-cadherin and CD44. Results The cell proliferation inhibition rate of the high-dose OM group was higher than that of the medium-dose and low-dose OM groups, the medium-dose group was higher than that of the low-dose OM group, the number of transmembrane cells in the OM groups was less than that in the negative control group (all P < 0. 05) , the high-dose OM group was less than that in the medium-dose and low-dose OM groups, and the medium-dose group was less than the low-dose group (all P <0. 05). The mRNA and protein levels of E-cadherin in the OM groups increased but the mRNA and protein levels of CD44 decreased (all P <0. 05). Conclusion OM could inhibit the proliferation, invasion and migration of HepG2 cells in vitro, and its mechanism may be related to the up-regulation of E-cadherin and down-regulation of CD44 expression. [ABSTRACT FROM AUTHOR]