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Background: A major barrier to achieving a favorable outcome of chronic HBV infection is a dysregulated HBV-specific immune response resulting from immunosuppressive features of FOXP3+ T cells. A better definition of FOXP3+ T cells is essential for improving the prognosis of HBV infection. We aimed to investigate the role of CD4+CXCR5−FOXP3+ T cells with CTLA4 expression in patients with chronic HBV infection. Methods: Treatment-naïve chronic HBV-infected patients, HBV-related hepatic failure, and a longitudinal cohort of chronic hepatitis B (CHB) patients with nucleos(t)ide analogue treatment were enrolled for analysis of CD4+CXCR5−FOXP3+ T cell responses by flow cytometry and single-cell RNA sequencing (scRNA-seq). Results: ScRNA-seq revealed that circulating CD4+CXCR5−FOXP3+ T cells presented distinct inhibitory features compared to spleen tissue. Meanwhile, patients with treatment-naïve chronic HBV infection or with HBV-related hepatic failure showed an upregulation of immune-suppressive features (PD-1, CTLA4, GITR) on CD4+CXCR5−FOXP3+T cells; in vitro analysis found HBeAg and HBcAg stimulation induced elevated levels of inhibitory molecules. Notably, the frequency of CTLA4+CD4+CXCR5−FOXP3+ T cells was positively correlated with HBV DNA levels, and longitudinal analysis demonstrated a high frequency of this subset at 12 weeks of antiviral treatment predicted unfavorable outcome in CHB patients. Conclusions: CTLA4+CD4+CXCR5−FOXP3+ T cells are related to unfavorable outcomes in HBV-infected patients; these data indicated that alleviating CTLA4+CD4+CXCR5−FOXP3+ T cells may improve the prognosis of HBV infection. [ABSTRACT FROM AUTHOR]