BACKGROUND: Oxymatrine has certain antiviral effects in the treatment of chronic hepatitis B (CHB), but its exact mechanism is unclear. The objective of the present study was to explore oxymatrineʼs antiviral mechanism by studying its effect on the hepatitis B virus (HBV) specific cytotoxic T lymphocyte (CTL) surface programmed death receptor-1 (PD-1) expression in CHB patients. METHODS: Sixty-five CHB patients who had HBV DNA>10 copies/ml, positive HBeAg, positive human leukocyte antigen (HLA)-A2, alanine aminotransferase (ALT) >2×upper limit of normal value (ULN) were randomly divided into two groups: treatment group (n=33), treated with an intravenous infusion of 600 mg oxymatrine in glucose solution once a day for a month, then with a 200 mg oxymatrine oral capsule three times a day, and a 200 mg silibin meglumine tablet three times a day; control group (n=32) patients were treated only with silibin meglumine tablet, method and dosage were the same as those of treatment group. Three months later, peripheral blood HBV-specific CTL surface PD-1 expression, HBV-specific CTL level, HBV DNA, HBeAg, and results of liver function tests were analyzed and compared. RESULTS: Three months post-treatment, in the treatment group, peripheral blood HBV-specific CTL surface PD-1 expression ((19.42+15.94)%) decreased significantly compared to the pretreatment level ((31.30+24.06)%; P<0.05), and decreased significantly compared to that of control group three months after treatment ((29.45+21.62)%; P <0.05). HBV-specific CTL level ((0.42+0.07)%) significantly increased compared with the pretreatment ((0.29+0.15)%; P<0.01), and the control group posttreatment level was (0.31+0.15)% (P <0.05). HBV DNA level in 11 cases became negative (HBV DNA<500 copies/ml, 33.33%), which was higher than that of the control group after treatment (two cases, 6.25%; χ=7.45, P<0.01), HBeAg of nine cases turned negative (27.27%), which was higher than that of the control group after treatment (one case, 3.13%; χ=.7.27, P<0.01). CONCLUSION: Oxymatrine could downregulate peripheral blood HBV-specific CTL surface PD-1 expression in CHB patients, increase HBV-specific CTL level, which may be one of the possible mechanisms by which oxymatrine clears or inhibits HBV in CHB patients.