Key Points • Inflammation-associated biomarkers (LY6E, EIF2AK2, IL15, and CXCL10) were firstly identified in Sjögren’s syndrome based on LASSO and SVM-RFE analyses. • CXCL10, EIF2AK2 and LY6E were prominently positively correlated with immature B cells, while IL15 were significantly negatively correlated with memory B cells in Sjögren’s syndrome. • LY6E, EIF2AK2, IL15, and CXCL10 were significantly more highly expressed in clinical Sjögren’s syndrome samples compared to healthy control samples, which was consistent with the analysis results of the GEO database. •LY6E, EIF2AK2, IL15, and CXCL10 might be used as the biomarkers for the treatment and diagnosis of Sjögren’s syndrome.