In a previous study, hepatitis B surface antigen (HBsAg) complexed to human anti-HBs immunoglobulins (HBIG) in excess of HBsAg was used as therapeutic vaccine to treat chronic hepatitis B patients and promising results were obtained. To study the mechanisms of this approach, mice were immunized with HBsAg or IC (immunogenic complex, i.e. HBsAg complexed with mouse polyclonal anti-HBs). Studies indicate that IC induced enhanced immune responses by increasing uptake of HBsAg through Fc receptors on antigen presenting cells and modulated HBsAg processing and presentation. This modulation led to stimulation of T cell responses, and increased production of IL-2 and IFN-gamma. Assay for antibody subclasses showed that higher ratio of IgG 2a was observed in the IC immunized group, which correlated with the production of lymphokine pattern. When alum was used as the adjuvant, though antibody response was enhanced, production of cytokines decreased. When DNA from a recombinant plasmid was added to IC as an adjuvant, the titer of anti-HBs was significantly higher than those in mice immunized only with the DNA or the IC. Since DNA immunization can induce both cellular and humoral immune responses, combined immunization using IC and DNA might serve as another type of therapeutic vaccine for viral hepatitis B.