Objective To investigate whether miR-122 is a target of oxymatrine against HBV. Methods HepG2.2.15 cells were incubated with culture medium containing different concentrations of oxymatrine. The cyto-toxicity of oxymatrine was determined by cck-8 assay. The surface antigen of HBV (HBsAg),antigenof HBV (HBeAg)and HBV DNA in supernatant and intracellular miR-122 were determined in HepG2.2.15 cells after incu-bation with culture medium containing oxymatrine for 72 h. Results The survival percentage of HepG2.2.15 cells under different concentrations of oxymatrine was higher than 95% when the concentration of oxymatrine was lower than 4 mg/mL. After treatment with oxymatrine for 72 h,the secretion of HBsAg and HBeAg,the level of HBV DNA in the supernatant were reduced. The intracellular miR-122 in oxymatrine experience group was 3.5 times higher than that in the negative control group. Conclusions Oxymatrine might be used to inhibit viral replication and antigen expression by enhancing the expression of miR-122 in HepG2.2.15 cells.