Objective: To investigate the mechanism of immune response to HBsAg mediated by CD4+ memory T lymphocytes in immunized HBV transgenic (Tg) mice. Methods: Peripheral CD4+ memory T lymphocytes were isolated and collected by magnetic bead sorting from C57BL/6 mice successfully immunized by hepatitis B vaccine. Adoptive immunization was performed for Tg mice by caudal vein injection, and the peripheral blood was collected at 4 and 8 weeks after adoptive immunization. Enzyme-linked immunosorbent assay was used to measure the levels of HBsAg, anti-HBs, interferon-γ (IFNγ), and interleukin-2 (IL-2), and immunohistochemistry was used to measure the level of HBsAg in the liver. The t-test was used for comparison of continuous data, and the chi-square test was used for comparison of categorical data. Results: Compared with the control group, the experimental group had a significant reduction in HBsAg titer[(243.5±12.4) ng/ml vs 0 ng/ml, t = 3.939, P = 0.011] and significant increases in the levels of anti-HBs [0 ng/ml vs (530.7±17.5) ng/ml, t = 4.414, P = 0.006 9], IFNγ [(12.25±2.9) pg/ml vs (38.8±6.8) pg/ml, t = 2.785, P = 0.049 6], and IL-2 [(11.3±3.5) pg/ml vs (82.3±9.2) pg/ml, t = 2.993, P = 0.040 2]. Conclusion: As for immune response to HBsAg mediated by CD4+ memory T lymphocytes in immunized HBV Tg mice, increases in the levels of IFNγ and IL-2 help to enhance humoral and cellular immunity and mediate the clearance of HBsAg in Tg mice.