Objectives To describe and compare the clinical and biological characteristics of subjects with primary Sjogren's syndrome (pSS) with and without anti-RNP antibodies. Methods Patients fulfilling the American College of Rheumatology (ACR)/EULAR 2016 criteria for pSS and having anti-RNP antibodies, without other connective tissue disease diagnosed and no anti-dsDNA antibodies were retrieved from the database from our French National Reference Center. These patients were compared with all other patients with pSS with negative anti-Sm, anti-RNP and anti-dsDNA antibodies. Results Overall, 21 patients with pSS positive for anti-RNP antibodies and 446 negative for anti-RNP antibodies were retrieved. Anti-RNP-positive patients had a lower median age at onset of pSS symptoms (41.0 vs 50.0 years, p=0.01), a higher median EULAR Sjogren's syndrome disease activity index at inclusion (8.0 vs 3.0, p<0.01), more frequently constitutional symptoms (14.3% vs 0.01%, p<0.01), myositis (19.0% vs 2.3%, p<0.01) and pulmonary (19.0% vs 5.7%, p=0.04) involvement. Moreover, anti-RNP-positive patients had higher median gammaglobulin levels (22.5 vs 13 g/L, p<0.01), more frequently anti-SSA antibodies (90.5% vs 67.1%, p=0.03), but less frequent lymphocytic sialadenitis with a focus score >= 1 (66.7% vs 85.5%, p=0.03). If the analysis is restricted to anti-SSA-positive patients, anti-RNP positivity is associated with the same clinicobiologic features except the pulmonary involvement. Conclusion Patients with pSS with anti-RNP antibodies displayed a more active systemic disease, with more frequent muscular and pulmonary involvement, and increased gammaglobulin level, compared with anti-RNP-negative patients.