CD4+ CXCR5+ T cell in peripheral blood is known as circulating follicular helper T cell (Tfh), which can produce interleukin 21 (IL-21). In the current study, we investigated changes of circulating Tfh and its correlation with IL-21 in diffuse large B-cell lymphoma (DLBCL). Circulating Tfh and its subtypes were detected by flow cytometry in the peripheral blood of 32 healthy donors and 62 DLBCL cases. Data demonstrated that percentage of circulating Tfh in CD4+ T cells was significantly increased in DLBCL (11.3 %) than in controls (8.5 %) (p = 0.001). Studying the subtypes of Tfh revealed that the upregulation of circulating Tfh was contributed by Tfh-Th2 subtype and Tfh-Th17 subtype. Also, we identified that prevalence of Tfh was significantly elevated in cases with advanced stages (stages III and IV). Interestingly, the elevation of circulating Tfh was negatively correlated with serum IL-21 in DLBCL patients. In addition, a positive correlation between circulating Tfh and IL-21 receptor on CD + 8 T cells was observed in patients. This study suggests involvement of circulating Tfh and IL-21 in the pathogenesis and progression of DLBCL and provides a potential target for treating this disease.