Systemic sclerosis (SSc) is a chronic multisystemic connective tissue disease characterized by progressive fibrosis affecting skin and internal organs. Despite serious efforts to unveil the pathogenic mechanisms of SSc, they are still unclear. High levels of reactive oxygen species (ROS) in affected patients have been shown, and ROS are suggested to play a role in fibrosis pathogenesis. In this study we evaluate ROS levels in nonfibrotic and fibrotic skin of patients with SSc and we compare them with those obtained from healthy controls. We enrolled nine SSc patients fulfilling the EULAR/ACR classification criteria and seven healthy controls. Patients included four men and five women with mean age of 46±10 years. Controls were matched by sex and age. All patients were affected by the diffuse cutaneous form of SSc and the ANA pattern anti-Scl70. Mean disease duration was 7.5±5 years. Skin involvement was evaluated by modified Rodnan skin score. Skin samples (4-mm punch biopsy) were taken from fibrotic skin and nonfibrotic skin of patients and from healthy controls as well. To detect ROS, specimens were analyzed immediately after sampling by electron paramagnetic resonance spectroscopy. Blood samples were drawn from all patients and controls to assess oxidative stress biomarkers. ROS levels (expressed as median and range, in nmol/L/min/mg of dry weight) were 24.7 (10.9–47.0) in fibrotic skin, 18.7 (7.3–34.0) in nonfibrotic skin, and 7.7 (3.5–13.6) in healthy control skin. ROS levels in fibrotic and nonfibrotic skin of SSc patients were significantly higher than in healthy controls (p=0.002 and p=0.009, respectively). ROS levels in fibrotic skin were raised in comparison to nonfibrotic skin, when samples related to each patient were compared (p=0.01). ROS levels in fibrotic skin were correlated with forced vital capacity (r=−0.75, p=0.02) and erythrocyte sedimentation rate (r=0.70, p=0.04). All other clinical and lab parameters showed no significant correlation. Compared to controls, blood from SSc patients showed lower ascorbate (vitamin C) levels (8 (3.8–9.8) vs 10.5 (9–19.1) mg/L, p=0.004) and higher lipid peroxides (873.5 (342–1973) vs 422 (105–576) μmol/L, p=0.004). Our results indicate the presence of high oxidative stress in both nonfibrotic skin and fibrotic skin of SSc patients, but with higher tendency in the latter. Raised ROS levels in nonfibrotic skin of SSc patients might be a hint of early involvement in skin fibrogenesis. However, a longitudinal prospective study is necessary for such proof.