To evaluate circulating T follicular helper (cTfh) cells and characterize their function in chronic-phase recipients after heart transplantation. Participants were divided into healthy control (HC, n=40), preoperative (Pre, n=40), and post-transplantation chronic-phase recipient (1-year, n=40) groups. The percentages of cTfh cell subsets and CD19+ B cell subsets were measured using flow cytometry. In vitro co-culture experiments were performed using cTfh cells and B cells isolated by fluorescence-activated cell sorting. Plasma concentrations of IL-21, chemokine ligand 13 (CXCL13), immunoglobulin G1 (IgG1), and immunoglobulin G3 (IgG3) were quantified using enzyme-linked immunosorbent assays (ELISA). cTfh and programmed cell death protein 1-positive (PD-1+) cTfh cells, the cTfh17/cTfh ratio, and class-switched memory B cells in peripheral blood were significantly increased in the 1-year group versus the HC and Pre groups (P<0.01), whereas the cTfh1/cTfh ratio and number of naïve B cells were significantly decreased in the 1-year group. Co-culture experiments showed that cTfh cells promoted B cell differentiation to plasmablasts. In the 1-year group, cTfh and PD-1+ cTfh cell numbers were positively correlated with plasmablasts in CD19+ B cells (P<0.01). The cTfh17/cTfh ratio was positively correlated with IgG3 concentrations in plasma (P<0.01). The plasma concentrations of interleukin-21 (IL-21) and CXCL13 in the 1-year group were increased compared to the HC and Pre groups (P<0.05). Chronic-phase recipients had increased proportions of CD4+CXCR5+ and CD4+CXCR5+PD-1+ cTfh cells, with a cTfh1-to-cTfh17 subtype conversion. An increased number of cTfh cells was positively correlated with B cell differentiation to plasmablasts, class-switched memory B cells, and greater IgG production. During the chronic phase, the proportion of cTfh cells increased and enhanced B cell responses. The cTfh-related soluble factors CXCL13 and IL-21 may regulate the immunopathogenesis of chronic immune injury. Thus, cTfh cells may drive long-term immune rejection in chronic-phase recipients after heart transplantation.