Background: Antiviral therapy is recommended for patients with immune-active chronic hepatitis B (CHB) to decrease the risk of liver-related complications. However, the outcomes of the pegylated IFN-α (PEG-IFN-α) therapy vary among CHB patients. We aimed to identify factors that can influence the outcomes in CHB patients who received antiviral PEG-IFN-α monotherapy.Methods: Thirty-two CHB patients who received PEG-IFN-α monotherapy were enrolled in this study. All of the patients underwent two liver biopsies at baseline and 6 months after the initiation of the therapy. CD8 + T cells, CD4 + T cells, CD68 + mononuclear cells, and PD-1 levels in the 64 liver biopsy specimens were examined via immunofluorescence.Results: The overall median frequency of CD8 + T cells in the liver tissues of 32 CHB patients significantly decreased at 6 months after the therapy initiation ( p < 0.01). In the FIER (fibrosis and inflammation response with HBeAg seroconversion) group, CD8 + PD-1 + T cells significantly decreased at 6 months ( p < 0.05), while CD8 + PD-1 - T cells had no significant difference. On the contrary, in the FIENR (no fibrosis and inflammation response and HBeAg seroconversion) group, CD8 + PD-1 - T cells significantly decreased after 6 months of PEG-IFN-α treatment ( p < 0.05), while CD8 + PD-1 + T cells had no significant difference. In addition, the levels of CD68 + mononuclear cells in the FIER group showed an overall increasing trend after treatment ( p < 0.05).Conclusions: The changes in the levels of CD8 + PD-1 + T cells and CD68 + mononuclear cells may be related to the response to PEG-IFN-α therapy.