Objective The biologic diagnosis of primary Sjögren disease (SjD) mainly relies on anti‐Ro60/SSA antibodies, whereas the significance of anti‐Ro52/TRIM21 antibodies currently remains unclear. The aim of this study was to characterize the clinical, serological, biologic, transcriptomic, and interferon profiles of patients with SjD according to their anti‐Ro52/TRIM21 antibody status. Methods Patients with SjD from the European PRECISESADS (n = 376) and the Brittany Diagnostic Suspicion of primitive Sjögren's Syndrome (DIApSS); (n = 146) cohorts were divided into four groups: double negative (Ro52 − /Ro60 − ), isolated anti‐Ro52/TRIM21 positive (Ro52 + ), isolated anti‐Ro60/SSA positive (Ro60 + ), and double‐positive (Ro52 + /Ro60 + ) patients. Clinical information; EULAR Sjögren Syndrome Disease Activity Index, a score representing systemic activity; and biologic markers associated with disease severity were evaluated. Transcriptome data obtained from whole blood by RNA sequencing and type I and II interferon signatures were analyzed for PRECISESADS patients. Results In the DIApSS cohort, Ro52 + /Ro60 + patients showed significantly more parotidomegaly (33.3% vs 0%–11%) along with higher β2‐microglobulin ( P = 0.0002), total immunoglobulin ( P < 0.0001), and erythrocyte sedimentation rate levels ( P = 0.002) as well as rheumatoid factor (RF) positivity (66.2% vs 20.8%–25%) compared to other groups. The PRECISESADS cohort corroborated these observations, with increased arthritis ( P = 0.046), inflammation ( P = 0.005), hypergammaglobulinemia ( P < 0.0001), positive RF ( P < 0.0001), leukopenia ( P = 0.004), and lymphopenia ( P = 0.009) in Ro52 + /Ro60 + patients. Cumulative EULAR Sjögren Syndrome Disease Activity Index results further confirmed these disparities ( P = 0.002). Transcriptome analysis linked anti‐Ro52/TRIM21 antibody positivity to interferon pathway activation as an underlying cause for these clinical correlations. Conclusion These results suggest that the combination of anti‐Ro52/TRIM21 and anti‐Ro60/SSA antibodies is associated with a clinical, biologic, and transcriptional profile linked to greater disease severity in SjD through the potentiation of the interferon pathway activation by anti‐Ro52/TRIM21 antibodies. image