Objective: To investigate the dynamic changes of peripheral blood T lymphocyte subsets and their correlation with HBsAg clearance in HBeAg-positive chronic hepatitis B (CHB) patients treated with recombinant human interferon α2b. Methods: A prospective study was conducted, enrolling 146 HBeAg-positive CHB patients. They were divided into an observation group (recombinant human interferon α2b treatment, n=73) and a control group [nucleos(t)ide analogue treatment, n=73]. Virological markers (HBV DNA, HBsAg, HBeAg), liver fibrosis parameters, and peripheral blood immunological indicators (T cell subsets, exhaustion/activation molecules, cytokines, and interferon-stimulated genes) were dynamically monitored at weeks 0, 12, 24, and 48 of treatment. Results: At 48 weeks of treatment, both the HBsAg clearance rate and the decline magnitude were greater in the observation group compared to the control group (P<0.05). Immunological data showed that the observation group had increased CD4+/CD8+ ratio and proportion of effector memory T cells (P<0.05). Multivariate Logistic regression confirmed that baseline HBsAg level, proportion of CD8+/PD-1+ cells, Treg proportion, and ISG15 upregulation fold were independent predictors of HBsAg clearance (OR=2.11, 95% CI:1.26~3.55). Conclusion: Recombinant human interferon α2b can synergistically promote HBsAg clearance by remodeling T cell subsets, reversing T cell exhaustion, and activating innate immune signaling. The specific immune features induced by recombinant human interferon α2b may provide a key basis for early prediction of functional cure.