The objective of this study was to explore the expression profile of the Interleukin (IL)-37/IL-18/IL-18BP/IL-18R axis in patients with primary Sjögren's syndrome (pSS). This study included 36 patients diagnosed with pSS, 13 patients presenting with sicca symptoms without confirmed pSS, and 14 healthy controls. Serum concentrations of IL-37, IL-18, IL-18BP, and IL-18R were measured using a sandwich ELISA. These levels were then correlated with relevant clinical and biological parameters. Furthermore, expression of the same cytokines was assessed in salivary gland biopsies via immunohistochemistry. No significant difference in serum IL-37 levels was observed among the three groups ( = 0.1695). However, serum levels of IL-18 and IL-18BP were significantly elevated in pSS patients compared to healthy controls ( < 0.0001), and these levels were strongly correlated. Immunohistochemical analysis revealed significantly higher expression of IL-37 in both the excretory ducts and inflammatory infiltrates of salivary glands in pSS patients compared to sicca patients. No correlation was found between IL-37 expression and the histological severity of glandular infiltration as assessed by the Chisholm score. In addition, an enhanced expression of IL-18, IL-18BP, and IL-18Rα was observed in the salivary glands of pSS patients. These findings suggest the potential contribution of the IL-37/IL-18/IL-18BP/IL-18R signaling axis in the pathogenesis of Sjögren's syndrome, particularly through its increased expression in salivary glands and correlation with disease-specific inflammatory markers. These findings may contribute to a better understanding of pSS immunopathology and suggest new avenues for biomarker development or therapeutic targeting.