summary. We examined whether combination therapy with thymosin-α1 and famciclovir would induce hepatitis B e antigen seroconversion in patients with chronic hepatitis B infection in the immune-tolerant phase without inducing significant hepatic necro-inflammation. We studied 32 hepatitis B e antigen positive patients in the immune-tolerant phase of infection, treated with 26-weeks combination therapy of famciclovir and thymosin-α1 (group 1). Thirty-two patients who received 26-weeks famciclovir monotherapy (group 2) and another 32 patients who received no treatment (group 3), served as controls. Peripheral blood mononuclear cell proliferation and cytokine secretion in response to recombinant HBV core and surface antigen andserial serum HBV-DNA, were assayed. No significant difference in adverse events were observed among the three groups. By week 26, the median reduction in group 1 (0.94 log10 copies/mL) was greater than group 2 (0.70 log10 copies/mL, P < 0.001). Five (15.6%) patients in group 1 at 52 weeks (median range 13–78 weeks) and none in group 2 or 3 experienced hepatitis B e antigen seroconversion (P = 0.053). Sustained serological clearance of hepatitis B e antigen was associated with activation of CD4 positive HBV-specific T-cell reactivity and were of T-helper 1. Hence combination therapy with immunomodulatory agents and nucleoside analogues should be explored.