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MDSCs expansion positively correlated with inflammation and involved in Th2 cell response during the progression of Sjögren's syndrome.Elimination of MDSCs improved SS-like syndrome and up-regulating Th2 cells, while MDSCs transplantation deteriorated SS and down-regulating Th2 cells in NOD mice.MDSCs and Th2 cells are crucial in SS and targeting to MDSCs and Th2 cells may lead to a novel therapeutic approach for SS.Myeloid-derived suppressor cells (MDSCs) can regulate various aspects of immune responses based on their potent immune-suppressive activity. Studies reported that MDSCs participated in many autoimmune diseases. However, the role of MDSCs in Sjögren's syndrome (SS) is unknown. In this study, we determined the frequencies and function of MDSCs in non-obese diabetic (NOD) mice and SS patients. The NOD mice were adoptively transferred with MDSCs or treated with anti-Gr1 antibody. Results showed that peripheral MDSCs increased significantly with the development of SS-like syndrome in NOD mice and the percentage of MDSCs was higher in SS patients than healthy controls. The SS-like syndrome aggravated after transfer of MDSCs in NOD mice. The deletion of MDSCs in NOD mice alleviated SS-like syndrome. Mechanistically, MDSCs down-regulated the percentages of Th2 cells in NOD mice and SS patients. In summary, our findings suggested that MDSCs exacerbated Sjögren's syndrome by inhibiting Th2 cells.