Increased circulating follicular helper-like T cells (cTfh) are reported in systemic lupus erythematosus (SLE) patients. However, whether B-cell lymphoma 6 (Bcl-6) is expressed in cTfh cells remains to be clarified. In this study, we found that the frequencies of CD4+CXCR5hiPD-1hicTfh, CD4+CXCR5hiPD-1hiICOShi, and CD4+CXCR5hiPD-1hiBcl-6+ populations were significantly increased in SLE patients (n=70) when compared with healthy controls (n=48). Surprisingly, only CD4+CXCR5hiPD-1hiBcl-6+ cTfh cells, rather than CD4+CXCR5hiPD-1hi population, were positively correlated with SLEDAI and anti-dsDNA antibodies. An elevated level of IL-21 was found in SLE CD4+ T cells. Moreover, IL-21 promoted the enrichment of TET2 in Bcl-6 promoter region and induced Bcl-6 expression. Therefore, Bcl-6 expression in cTfh cells may represent a reliable marker for the disease activity in SLE.