Immune elimination of hepatitis B virus (HBV) during antiviral therapy depends on the activation of T-cell responses, which are generally impaired in chronic hepatitis B. HBV-specific T helper (Th)-cell reactivity has been assessed post-treatment in liver and peripheral blood of 18 anti-HBe-positive patients with chronic hepatitis B administered combined ribavirin/interferon alfa (IFN-alpha) therapy. The results showed that patients with undetectable HBV DNA by quantitative polymerase chain reaction under combination therapy were able to mount an HBV-specific CD4(+) Th-cell proliferative response and such T-cell reactivity is detectable 1 year after HBV DNA clearance. Hepatitis B virus core (HBcAg) and e (HBeAg) antigen-specific Th-cell proliferation was found more frequently in the liver and peripheral blood in those patients who sustained the alanine aminotransferase (ALT) normalization together with HBV DNA loss. However, HBV-specific IFN-gamma production in vitro in peripheral blood mononuclear cells augmented in 4 of 5 sustained responders and all 13 nonresponders, interleukin 10 (IL-10) production decreased in all 5 sustained responders but increased in 7 of 13 nonresponders. Furthermore, intrahepatic HBcAg plus HBeAg-specific Th-cell proliferation only occurred in sustained responders (2 of 3, 67%, vs. 0 of 9; P =.045) whose cells showed in vitro significantly increased productions in HBcAg/HBeAg-specific IFN-gamma and IL-12 compared with nonresponders in whom IFN-gamma and IL-12 productions decreased together with increased IL-10 secretion. In conclusion this study indicates that combined therapy with ribavirin and IFN-alpha for chronic hepatitis B not only significantly reduces viremia levels but also induces lasting CD4(+) T-cell proliferation and Th1 cytokine release at the site of infection, which may lead to sustained eradication of the HBV.