To study the responses of chronic hepatitis B patients to yeast-derived HBsAg-HBIG complexes (YIC) and the mechanisms involved, twenty HBeAg-positive chronic hepatitis B patients were immunized with 60microg of YIC or alum as the control at 4-week intervals, for 24 weeks. Five of ten patients responded to 60microg YIC immunization showing > or =2 logs decrease of serum HBV DNA with loss or marked reduction of HBeAg and appearance of anti-HBe; two of these patients developed anti-HBs. Flares of alanine aminotransferase were observed in 4 of the 5 responders, and in 2 out of 10 control patients. HBsAg-stimulated peripheral blood mononuclear cells (PBMCs) secreted Th1/Th2 cytokines around 24 weeks after immunization. Dendritic cells incubated with YIC showed the highest levels of IL-12 secretion and up-regulation of functional markers. Thus, the therapeutic effect of YIC is associated with cytolytic and non-cytolytic responses in patients.