Background <p>This study aimed to investigate the expression profile and clinical relevance of microRNA-155 (miRNA-155) in patients with primary Sjögren’s disease (pSD).</p> Methods <p>We enrolled 75 pSD patients, categorized into untreated (<i>n</i> = 41) and treated (<i>n</i> = 34) subgroups, along with 40 healthy controls. Plasma miRNA-155 levels were quantified using quantitative real-time PCR (qRT-PCR) in a subset of participants (24 pSD patients, 10 controls). Clinical and immunological parameters, including erythrocyte sedimentation rate (ESR), anti-SSB antibodies, and organ involvement, were analyzed for correlations with miRNA-155 expression.</p> Results <p>miRNA-155 expression was significantly downregulated in pSD patients compared to controls (<i>P</i> = 0.001). Treated patients had significantly higher miRNA-155 levels than untreated patients (<i>P</i> = 0.045), although both were lower than controls. Subgroup analyses revealed elevated miRNA-155 levels in patients with higher ESR (<i>P</i> = 0.045), anti-SSB seropositivity (<i>P</i> = 0.001), and Chisholm grade III labial gland pathology (vs. grade IV, <i>P</i> = 0.049). Conversely, patients with interstitial lung disease exhibited reduced miRNA-155 expression (<i>P</i> = 0.007). Positive correlations were observed between miRNA-155 and ESR (<i>r</i> = 0.630, <i>P</i> = 0.001) and IgA levels (<i>r</i> = 0.542, <i>P</i> = 0.009). An exploratory analysis suggested lower baseline miRNA-155 levels may be associated with a greater therapeutic reduction in ESR.</p> Conclusions <p>pSD patients demonstrate significantly decreased plasma miRNA-155 expression. These levels are associated with treatment status, anti-SSB antibody production, pulmonary involvement, and labial gland pathology. miRNA-155 levels are also correlated with systemic inflammation and IgA dysregulation, suggesting its potential as a complex biomarker in pSD pathogenesis and for monitoring disease activity.</p>