Therapeutic efficacy of HBsAg-anti-HBs-recombinant DNA harboring hepatitis B virus (HBV) S gene complex was compared with three other therapeutic vaccine candidates (recombinant HBsAg, HBsAg complexed to anti-HBs antibodies and naked plasmid DNA encoding the HBV S gene). After four injections at 3-week intervals, the most pronounced decrease of serum HBsAg, the highest titer of anti-HBs response, the highest level of interferon-gamma produced by splenocytes and potent cytotoxicity T cell response were observed in the HBsAg-anti HBs-sDNA immunized group. Reduced expression of HBsAg in hepatocytes was also shown. The therapeutic mechanism of HBsAg-anti-HBs-DNA was speculated as modulation of HBsAg presentation via both endogenous and exogenous pathways.