Background: ThePCSK3gene encodes for the protease enzyme Furin, which promotes proteolytic maturation of important regulators of the immune response, and also enhances the secretion of interferon-γ (IFN). Several studies have suggested its possible involvement in the pathogenesis of chronic inflammatory diseases. Methods: We investigated thePCSK3gene expression level in peripheral blood mononuclear cells isolated from Sjögren’s Syndrome (SS) patients and healthy controls and we evaluated a possible correlation withIFN-γgene expression. Moreover, we also explored the variability of twoPCSK3genetic polymorphisms (rs4932178 and rs4702) to evaluate a possible association between these polymorphisms and the expression levels of this gene. Results: We observed, by RT-qPCR, that thePCSK3expression level was significantly higher in SS patients compared to the controls (p= 0.028), and we confirmed a positive correlation betweenPCSK3andIFN-γexpression levels (p< 0.001). Moreover, we reported that the variant homozygous genotype of rs4932178 SNP is associated with a higher expression of thePCSK3gene (p= 0.038) and with the SS susceptibility (p= 0.016). Conclusions: Our data suggest that Furin could play a role in SS development, also promoting IFN-γ secretion.