Objectives: To investigate the dynamic change of follicular T helper cells (T-FH) in patients with malignant lymphoid disease (MLD) and to explore its clinical significance. Methods: The dynamic change of T-FH cells, ICOS+- and PD-1(+) T-FH cells at pretreatment and different treatment periods was determined by flow cytometry in 85 MLD patients. Concentration of interleukin 21 (IL-21) was evaluated by ELISA, and the correlation between clinical prognosis and the ratio of TFH cells was analyzed. Results: Significantly increased ICOS+- and PD-1(+) T-FH cells were found in MLD patients at pretreatment compared to healthy controls. Decreased or even close to normal levels of ICOS+- and PD-1(+) T-FH cells were found at the end of treatment. However, in the patients with progressive disease, high levels of ICOS+- and PD-1(+) T-FH cells were found. Moreover, a significantly increased plasma IL-21 level was found in MLD patients. Negative correlation was found between the level of ICOS+-, PD-1(+) T-FH cells, as well as IL-21 and the prognosis of MLD. Conclusions: Significantly increased T-FH cell ratios were found in patients with MLD, and decreased T-FH cells ratios could be expected in those treatment-effective patients, which could be used as the therapeutic efficacy index.