The study identified and validated necroptosis-related genes in peripheral blood mononuclear cells (PBMC) of patients with Sjögren's disease (SjD) using bioinformatic analysis of data from the GEO database (GSE48378) and subsequent validation. In PBMCs of SjD patients, 24 necroptosis-related genes were found to interact closely according to PPI analysis. Of the ten selected genes (including the top 8 and 2 key ones), 7 were elevated (TNFRSF10, STAT3, NLRP3, RIPK, MLKL, TLR4, EIF2AK2), which was confirmed by RT-PCR in the validation cohort. HMGB1 levels in the peripheral blood of SjD patients were increased and positively correlated with ESSDAI clinical scores. Electron microscopy confirmed morphological features of necroptosis in PBMCs of SjD patients. GO and KEGG analyzes showed enrichment of the necroptosis pathway in PBMCs in SjD. ELISA detected increased concentrations of HMGB1 and correlations of MLKL or HMGB1 with clinical parameters of SjD were evaluated.