An aberrant immune response has been implicated in the pathogenesis of osteoarthritis (OA). However, the role of peripheral blood follicular helper T (TFH) cells in the pathogenesis of OA has yet to be elucidated. The purpose of the present study was to examine the role of TFH cells and serum interleukin‑21 (IL‑21) in the pathogenesis of OA. Frequency of peripheral blood inducible costimulator (ICOS)+, programmed death 1 (PD‑1)+, and IL‑21+ CXCR5+CD4+ T cells in 40 patients with OA and 13 healthy controls (HCs) were examined by flow cytometry. The disease state in individual patients was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Concentrations of serum IL‑21, interferon‑γ (INF‑γ), IL‑4, IL‑17A, and C‑reactive protein (CRP) were determined, and the erythrocyte sedimentation rate (ESR) was measured. The percentages of CXCR5+CD4+ cells, PD‑1+CXCR5+CD4+, ICOS+CXCR5+CD4+ and IL‑21+CXCR5+CD4+ T cells in OA patients were significantly higher than those in the HCs. Furthermore, serum IL‑21, IL‑17A and IFN‑γ levels in OA patients were significantly higher than those in HCs. Expression of IL‑21+TFH cells in OA patients demonstrated a positive correlation with OA disease activity, CRP levels and WOMAC. TFH cells and IL‑21 appear to serve an important role in the progression of OA. IL‑21+TFH cells may prove to be a marker of OA disease activity.