Donor-specific anti-HLA antibodies (DSAs) are a major risk factor associated with renal allograft outcomes. As a trigger of B cell antibody production, T follicular helper cells (Tfhs) promote DSA appearance. We measured circulating Tfh (cTfh) levels on the day of transplantation and one year after transplantation in blood from a prospective cohort of 237 renal transplantation patients without DSA during the first year post-transplantation. Total cTfh were characterized as CD4+CD45RA-CXCR5+, and the three following subsets of activated cTfh were analyzed: CXCR5+PD1+, CXCR5+PD1+ICOS+ and CXCR5+PD1+CXCR3-. Immunizing events (previous blood transfusion and/or pregnancy) and the presence of class II anti-HLA antibodies were associated with increased frequencies of activated CXCR5+PD1+, CXCR5+PD1+ICOS+ and CXCR5+PD1+CXCR3- cTfh subsets. By contrast, ATG-depleting induction and calcineurin inhibitor treatments decreased the total level of cTfhs, and activated cTfh subsets were increased at one year post-transplantation. In multivariate survival analysis, we reported a decrease in activated CXCR5+PD1+ICOS+ at one year after transplantation in the blood of DSA-free patients and a significant association with the risk of developing dnDSA after the first year (p=0.018, HR =0.39), independent of HLA mismatches (p=0.003, HR =3.79). These results highlight the importance of monitoring activated Tfhs in patients early after transplantation and show that current treatments cannot provide early, efficient prevention of Tfh activation and migration. These findings indicate the need to develop innovative treatments to specifically target Tfhs to prevent DSA appearance in renal transplantation.