Treatment options for chronic hepatitis B (CHB) infection are extremely limited. CXCR5 CD8 T cell is a novel cell subtype and could possess strong cytotoxic properties in HIV infection. In this study, we investigated the role of CXCR5 CD8 T cells in CHB patients. Compared to healthy individuals, both CHB patients and hepatitis B virus (HBV)-infected hepatocellular carcinoma patients presented significant upregulation of CXCR5 CD8 T cells in peripheral blood, in which CXCR5 CD8 T cells were negatively correlated with the frequency of CXCR5 CD4 T cells in CHB patients. After PMA+ionomycin stimulation, CXCR5 CD8 T cells from CHB patients presented significantly higher transcription level of interferon gamma (IFN-γ), interleukin 10 (IL-10), and IL-21, as well as higher IL-10 and IL-21 protein secretion, than CXCR5 CD8 T cells. Unlike CXCR5 CD4 T cells, when incubated with naive CD19CD27 B cells, CXCR5 CD8 T cells alone did not upregulate IgM, IgG, and IgA secretion. However, addition of CXCR5 CD8 T cells in B cell-CXCR5 CD4 T cell coculture significantly increased the levels of secreted IgG and IgA, demonstrating that CXCR5 CD8 T cell could indirectly offer B cell help. Furthermore, high frequencies of CXCR5 CD8 T cells tended to associate with low HBV DNA load, and the frequency of CXCR5 CD8 T cells was negatively correlated with alanine aminotransferase (ALT) level. Together, these results suggested that CXCR5 CD8 T cells were involved in the antiviral immune responses in CHB and could potentially serve as a therapeutic candidate.