The objectives of this study were to examine the serum levels of interleukin (IL)-37 and its clinical association in patients with primary Sjögren's syndrome (pSS) and to investigate whether or not IL-37 participates in the regulation of the pathogenesis of pSS. ELISA was used to analyse the serum levels of IL-37, total IL-18 and IL-18 binding protein (IL-18BP). The level of free IL-18 was calculated based on the mass action law. The correlations between the IL-37 serum levels with the laboratory values and the total IL-18 and IL-18BP serum levels were analyzed by a Spearman's correlation test. The serum levels of IL-37 in the patients with pSS were significantly increased compared with the healthy controls (HCs). The levels were especially elevated in the patients with pSS with positive anti-Ro/SSA and/or anti-La/SSB antibodies. Furthermore, the patients with pSS showed high serum levels of total IL-18, free IL-18 and IL-18BP compared with the HCs. Strikingly, the IL-37 levels were significantly positively correlated with the antibody levels in the patients with pSS, including rheumatoid factor, anti-Ro/SSA, and anti-La/SSB and the total IL-18 and IL-18BP serum levels. The serum levels of IL-37, which were correlated with antibody production and the serum levels of total IL-18 and IL-18BP, were elevated in the patients with pSS. IL-37, an important anti-inflammatory cytokine, may participate in the regulation of the pathogenesis of pSS.