Objective: To investigate the effects of the multi-glycosides of Tripterygium wilfordii (GTW) on Sjögren's syndrome (SS) in the non-obese diabetic (NOD) mouse model. Methods: Twenty-seven 8-week-old, female NOD mice were divided into the GTW group, the hydroxychloroquine (HCQ) group, and control (normal saline) group, and received corresponding treatment for 16 weeks. The treatment-induced changes in stimulated total saliva flow rate (STFR), level of serum anti-SSA/SSB, ratio of regulatory T (Treg) cells, histology of the submandibular gland (SMG) and the gene expression profile that is related to inflammation and autoimmunization were evaluated. Results: Compared to the untreated (control) mice, STRF, SMG index and Treg/CD4+ cell ratio were significantly higher, whereas anti-SSA, anti-SSB and lymphoid foci were remarkably lower in GTW-treated mice. HCQ-treated mice showed similar results except SMG index was not different from the untreated mice. NOD mice showed 19.03% altered gene expression with maturation from the age of 8 weeks to 24 weeks. Treatment with HCQ and GTW reduced the change in gene expression to 13.09% and 7.14%, respectively. Conclusion: GTW is as effective as HCQ in the treatment of Sjögren's syndrome in the NOD mouse model. Keywords: multi-glycoside of Tripterygium wilfordii, NOD mouse model, Sjögren's syndrome