ObjectiveTo identify and characterize a novel systemic sclerosis (SSc)–related autoantibody directed against a complex consisting of RuvBL1 and RuvBL2 (RuvBL1/2) and to assess its clinical correlations.MethodsWe first analyzed 316 consecutive patients with SSc who were evaluated at Kanazawa University Hospital. Controls included 290 patients with other connective tissue diseases, interstitial lung disease alone, or autoimmune hepatitis, and 50 healthy subjects. Autoantibody specificities were analyzed using RNA and protein immunoprecipitation assays. Autoimmune targets were affinity purified using patients' sera and subjected to liquid chromatography mass spectrometry. SSc patients in another institution in Japan and the University of Pittsburgh cohort were also included in analysis for evaluating clinical correlations.ResultsBy protein immunoprecipitation assay, 6 SSc sera (1.9%) reacted with doublets with molecular weights of ∼50 kd. Liquid chromatography mass spectrometry of the partially purified autoantigen and additional immunoblot‐based analyses revealed that this antibody specificity recognized RuvBL1/2. Anti‐RuvBL1/2 antibody was exclusively detected in SSc patients. SSc patients with anti‐RuvBL1/2 in both the Japanese and Pittsburgh cohorts consistently had higher frequencies of SSc in overlap with myositis and diffuse skin thickening than those without anti‐RuvBL1/2. Compared with other autoantibodies related to SSc/myositis overlap (anti–PM‐Scl and anti‐Ku), anti‐RuvBL1/2 was distinctive in terms of its associations with older age at SSc onset, male sex, and a high frequency of diffuse cutaneous involvement.ConclusionAnti‐RuvBL1/2 antibody is a novel SSc‐related autoantibody associated with a unique combination of clinical features, including myositis overlap and diffuse cutaneous involvement.