Objective. Exercise limitation in patients with systemic sclerosis (SSc) is often multifactorial and related to complications such as interstitial lung disease (ILD), pulmonary vasculopathy (PV), left ventricular dysfunction (LVD), and/or peripheral/muscular limitation (PML). We hypothesized that cardiopulmonary exercise testing (CPET) could not only suggest and rank competing etiologies, but also highlight peripheral impairment. Methods. Clinical, resting pulmonary function testing, and CPET data from patients with SSc referred for exercise limitation between October 2009 and November 2015 were retrospectively analyzed in this bi-center study. Patients were categorized as having ILD, PV, LVD, and/or PML based on CPET response patterns and the diagnoses were matched with results from the reference investigations. The latter consisted of transthoracic echocardiography, chest computed tomography scan, and right heart catheterization (RHC). Results. Twenty-seven patients presented with CPET profiles consistent with ILD (n = 16), PV (n = 15), LVD (n = 5), and PML (n = 19). None of the subjects had a normal CPET profile. There was a statistically significant negative correlation between resting DLCO, on the one hand, and dead space to tidal volume ratio and alveolar–arterial gradient [P(Ai-a)O2] on the other (p < 0.005). CPET identified 90% of patients with a mean pulmonary arterial pressure at rest ≥ 21 mmHg measured by RHC (n = 10). Peak P(Ai-a)O2, taken independently from other variables, was crucial in distinguishing subjects with ILD from those without ILD (p < 0.05). Conclusion. CPET is useful for the characterization of multifactorial exercise limitation in patients with SSc and in identifying SSc-related complications such as ILD and PV. This study also identifies PML as an underestimated cause of exercise limitation.