Given the clinical significance of hepatitis B e antigen (HBeAg) seroconversion in chronic hepatitis B virus (HBV) infection, it is critical to elucidate the mechanisms regulating this process. In the present study, we found that the frequency of circulating chemokine (C‐X‐C motif) receptor 5 (CXCR5)⁺CD4⁺ T cells was higher in patients who had achieved HBeAg seroconversion in both cross‐sectional (P < 0.001) and longitudinal (P = 0.009) studies. These cells were able to produce a significantly higher level of intracellular interleukin 21 (IL‐21) after stimulation with HBV peptides in patients with telbivudine‐induced HBeAg seroconversion (P = 0.007). Furthermore, sorted CXCR5⁺CD4⁺ T cells from HBeAg seroconverters boosted a higher frequency of antibody against hepatitis B e antigen (anti‐HBe)‐secreting B cells in coculture assay (P = 0.011). Of note, the increase in frequency of anti‐HBe‐secreting B cells was abrogated by soluble recombinant IL‐21 receptor‐Fc chimera (P = 0.027), whereas exogenous recombinant IL‐21 enhanced this effect (P = 0.043). Additionally, circulating CXCR5⁺CD4⁺ T cells shared similar phenotypic markers, and were positively correlated in frequency with, splenic follicular T helper cells. Conclusion: Circulating CXCR5⁺CD4⁺ T cells, by producing IL‐21, may have a significant role in facilitating HBeAg seroconversion in patients with chronic HBV infection. (Hepatology 2013;58:1277–1286)