Background <p>Primary Sjögren’s syndrome (pSS), a systemic autoimmune disorder, is recognized by immune dysregulation and chronic inflammation. Though telomere attrition has been linked to various immune-related diseases, its relationship with pSS pathogenesis remains poorly understood. This research seeks to explore the relationship between peripheral blood leukocytes’ telomere length and the susceptibility to pSS, thereby offering insights into the potential role as a biomarker.</p> Methods <p>181 participants, comprising pSS patients (<i>n</i> = 87) and healthy controls (<i>n</i> = 94) were involved in this study. Relative length of leukocyte telomere (<i>T</i>/<i>S</i> ratio) was quantified by a validated quantitative PCR protocol. To define the independent effect of telomere length on pSS susceptibility, logistic regression analyses, including univariate and multivariable, were performed. In addition, generalized additive modeling (GAM) was applied to identify possible nonlinear dose–response patterns.</p> Results <p>pSS patients demonstrated significantly shorter telomere lengths than healthy controls (mean <i>T</i>/<i>S</i> ratio: 0.8 ± 0.35 vs. 1.01 ± 0.49, <i>P</i> = 0.0019). Decreased length of telomere was strongly linked to a higher likelihood of pSS occurrence (OR = 0.31, 95% CI: 0.15–0.66, <i>P</i> = 0.0021). This relationship stayed statistically meaningful, albeit slightly weakened, after accounting for clinical characteristics and therapeutic variables. Moreover, nonlinear modeling suggested that progressive telomere shortening corresponded to a rising probability of developing pSS, implying a potential mechanistic contribution of telomere erosion to disease development.</p> Conclusion <p>This cross-sectional study indicates that reduced telomere length in peripheral blood leukocytes is linked to an elevated likelihood of developing pSS, suggesting that telomere dynamics could function as a promising biomarker for early detection and risk assessment. Future longitudinal studies are warranted to confirm causality and assess telomere-targeted interventions.</p> <p><Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry align="left" nameend="c2" namest="c1"> <p><b>Key Points</b></p> <p>• <i>Leukocyte telomere shortening serves as a clinically relevant biomarker in pSS.</i></p> <p>• <i>Nonlinear dynamics link telomere attrition to immune dysregulation.</i></p> <p>• <i>Telomere length shows complex interaction with disease stage and therapeutics.</i></p> </entry> </row> </tbody> </tgroup> </Table></p>