Objective.Autoreactive antibody responses, including the use of several isotypes of autoantibodies, have been shown to be associated with clinical outcome in several rheumatic autoimmune diseases. The goals of this study were to evaluate whether (1) anticentromere antibody (ACA)– and antitopoisomerase antibody (ATA)–specific isotype expression, and (2) organ involvement are associated with the degree of microangiopathy in systemic sclerosis (SSc).Methods.ACA and ATA IgG, IgM, and IgA levels were measured in baseline serum samples of ACA IgG–positive (+) and ATA IgG+ patients with SSc. The degree of microangiopathy was determined based on nailfold videocapillaroscopy (NVC) images collected at the same point in time. Logistic regression analyses with autoantibodies, clinical characteristics, isotype expression, and ACA and ATA IgG, IgM, and IgA levels as independent variables, and NVC pattern as the dependent variable were performed.Results.In 164 patients, isotype levels and degree of microangiopathy were evaluated. Logistic regression confirmed the association of the degree of microangiopathy with the presence of digital ulcers (OR 3.07, 95% CI 1.43–6.60), interstitial lung disease (OR 3.41, 95% CI 1.11–10.61), and pulmonary arterial hypertension (OR 5.58, 95% CI 2.05–17.81). ATA positivity was associated with more severe microangiopathy (OR 2.09, 95% CI 1.05–4.13). Patients who expressed solely ACA IgG showed a trend towards less severe microangiopathy compared to patients also expressing ACA IgM and/or IgA. Levels of ACA IgG and ATA IgM were found to be associated with microangiopathy severity.Conclusion.We observed an association between ACA and ATA responses and the degree of microangiopathy in SSc. These findings might indicate that the breadth of the autoimmune response, as reflected by autoantibody production and microvascular damage, interacts in the pathophysiology of SSc.