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Introduction To investigate the demographic and clinical features of systemic sclerosis (SSc) patients with anti-U1RNP antibodies using the European Scleroderma Trials and Research (EUSTAR) database.Material and Methods SSc patients fulfilling SSc classification criteria with available data on anti-U1RNP antibodies were analyzed. Clinical characteristics were collected when the status of anti-U1RNP antibodies was first recorded and patients positive and negative for anti-U1RNP antibodies were compared by univariable analysis. Associations between anti-U1RNP status and organ involvement were assessed by multivariable logistic regression, adjusted for covariables. Multiple imputation was used to handle missing data.Results A total of 8391 patients were eligible for this analysis, among which 408 (4.9%) patients were positive for anti-U1RNP antibodies. By multivariable analysis, anti-U1RNP antibodies were confirmed to be independently associated with earlier disease onset (OR 0.96, 95% CI 0.95 to 0.97), synovitis (OR 1.82, 95% CI 1.20 to 2.77), pulmonary hypertension on echocardiography (OR 2.13, 95% CI 1.41 to 3.20), proteinuria (OR 2.25, 95% CI 1.29 to 3.93), lower mRSS (OR 0.95, 95% CI 0.93 to 0.98) and elevated ESR (OR 1.48, 95% CI 1.03 to 2.12). Besides, there was a negative association with white race (OR 0.25, 95% CI 0.17 to 0.37).Conclusions This is the largest cohort of SSc patients positive for anti-U1RNP antibodies reported so far. It defines a distinct clinical phenotype, with predilection for non-white race, younger disease onset, inflammation and articular, cardiopulmonary or renal involvement. The detection of anti-U1RNP antibodies in SSc patients might be helpful for risk stratification in clinical practice.