Both host immunity and hepatitis B virus (HBV) contribute to the therapeutic response to interferon (IFN)-α treatment in chronic hepatitis B (CHB) based on the immune modulation function to eliminate virus, while neither viral load nor cytokine alone could reflect the complex interaction between host immune response and virus. This study aimed at exploring a parameter of combined immunological and virological indexes to predict the response profile to IFN-α treatment in patients with CHB. Biochemical (alanine transaminase), virological (HBV DNA load, HBsAg, HBeAg), and immunological [IFN-γ, tumor necrosis factor (TNF), interleukin (IL)-2, IL-4, IL-6, and IL-10] indexes were dynamically monitored (at baseline, 2, 4, 8, 12, 24, 36, 48, and 72 weeks) in 41 patients who received a 48-week IFN-α treatment. First, we found that responders displayed an elevation in both Th1 and Th2 type cytokines from baseline to 4 weeks. What is more, the HBV DNA load at the baseline and IL-10 at 4 weeks showed significant differences between responders and nonresponders and were highly associated with the response to IFN-α treatment. More importantly, IL-10/HBV DNA was identified as a positive predictor for response to IFN-α treatment (odds ratio=5.785) by logistic regression analysis. We show here that the IL-10/HBV DNA ratio, a parameter of combined immunological and virological factors, can be useful in predicting the response to IFN-α treatment in CHB.