[Objective]To evaluate the efficacy of Yiqi Yangyin Quyu Prescription in the treatment of primary Sj?gren's syndrome(pSS),and study the epigenetic markers related to the efficacy of traditional Chinese medicine through whole genome bisulfate sequencing(WGBS)technology.[Methods]Fifty patients with pSS were included,including 30 in Chinese medicine group and 20 in western medicine group.Clinical information before treatment and 12 weeks after treatment was evaluated,and the therapeutic effect was analyzed.Three effective patients were selected from Chinese medicine group and their whole blood samples before and after Chinese medicine treatment were subjected to WGBS.Through methylation site analysis,gene ontology(GO)of differentially methylated genes,Kyoto Encyclopedia of Genes and Genomes(KEGG),and molecular signature database(MSigDB)enrichment analysis,efficacy-related differentially methylated genes and pathways were identified.[Results]Compared with pre-Chinese medicine treatment group,the group treated with Chinese medicine after 12 weeks showed a significant decrease in Sj?gren's syndrome disease activity index(SSDAI),erythrocyte sedimentation rate(ESR),and immunoglobulin G(IgG)level(P<0.05).Compared with pre-western medicine treatment group,the SSDAI and ESR levels in western medicine treatment group after 12 weeks decreased significantly(P<0.05).There was no statistically significant difference in SSDAI,ESR,and other indicators between the group treated with Chinese medicine after 12 weeks and the group treated with western medicine after 12 weeks(P>0.05).WGBS identified a total of 29 differentially methylated regions(DMRs),mainly concentrated at the sites of repetitive elements and protein coding genes,covering a total of 68 genes,including three RNA categories:mRNA,long noncoding RNA(lncRNA),and circRNA.Enrichment analysis suggested that the therapeutic effect was closely related to pathways such as antigen processing and presentation,interferon related pathways,and helper T cell(Th)1 and Th2 cell differentiation.[Conclusion]Yiqi Yangyin Quyu Prescription can regulate DNA methylation,thereby inhibiting the immune response in patients with pSS and exerting therapeutic effects.