The molecular mechanisms of primary Sjogren's syndrome (pSS) are poorly understood. In this study, we explored the role of the IL-33/ST2 axis in the development of pSS. In the mouse model of experimental Sjogren's syndrome, we found that the saliva flow rate at weeks 4 and 30 was preserved in IL-33(-/- )and ST2(-/-) mice, compared with that of wild-type mice. At week 30 of experimental Sjogren's syndrome induction, the histological score, anti-nuclear Ab levels, and numbers of Th1 and B cells in draining lymph nodes of the salivary gland were lower in the IL-33(-/-) and ST2(-/-) mice, whereas Th17 cells and regulatory T cells were not changed. Primary salivary gland epithelial cells expressed the IL-33 receptor ST2. After stimulation with rIL-33, salivary gland epithelial cells increased the transcriptional levels of CD86 and CCL2, accompanied by the activation of the NF-kappa B inflammatory pathway. There was a synergistic effect between rIL-33 and rIL-12 in augmenting the production of IFN-gamma in CD4(+) T cells. In the pSS patients, the expression of IL-33 was elevated in the labial salivary gland, with the number of IL-33(+) cells positively correlated with the score of the EULAR (European Alliance of Associations for Rheumatology) Sjogren's syndrome disease activity index (ESSDAI). ST2 was highly expressed in the cytoplasm of ductal epithelial cells, with low levels of expression in lymphatic infiltration sites. Our data suggest that the IL-33/ST2 axis may promote the development of pSS by enhancing salivary epithelial cell activation and the type 1 immune response.