Abstract: Objective To analyze the characteristics of lymphocyte phenotypes in hepatitis B virus (HBV) transgenic mice and the effect of exogenous interferon-α on virological profiles and lymphocytes phenotypes of the mice. Methods HBV transgenic mice and wild-type (WT) mice were examined for serum levels of HBsAg, HBcAb, IL-21, and IL-6 using ELISA. The frequencies of CD4+T and CD19+B cells separated from the liver, spleen, and peripheral blood were detected by flow cytometry. Nine HBV transgenic mice were injected subcutaneously with recombinant mouse interferon alpha (rmIFN-α) and another 9 transgenic mice were injected with PBS, and their HBsAg, HBV DNA, IL-6, and IL-21 levels and frequencies of peripheral blood CD4+T and CD19+B cells were detected. Results HBV transgenic mice showed a high level of HBsAg with a detectable level of HBcAb and significantly increased serum levels of IL-21 and IL-6 as compared with WT mice (P<0.05). The transgenic mice had a significantly lower frequency of CD4+ T cells in the peripheral blood, liver and spleen (P<0.05) but a significantly higher frequency of CD19+ B cells in the liver (P<0.05). An inverse correlation between intrahepatic CD4+ T cell frequency and serum HBsAg level while a positive correlation between intrahepatic CD19+ B cell frequency and HBcAb level were found in HBV transgenic mice. Administration of rmIFN-α significantly increased the frequencies of CD4+ T and CD19+ B cells in the peripheral blood and the serum level of IL-6 in HBV transgenic mice (P<0.05). Conclusion HBV transgenic mice have lymphocyte subset dysregulation and exogenous interferon-α can modulate the immune function of the mice by regulating the frequencies of lymphocyte subsets.