Systemic sclerosis (SSc) is a complex disease characterized by vascular injury with endothelial cell and platelet activation, immune dysregulation with inflammatory cytokines and fibroblast activation. The Raynaud phenomenon and puffy hands and fingers are common early manifestations of the disease that have a negative impact on patients' quality of life. Vasodilators such as calcium channel blockers, PDE5 inhibitors, and prostacyclin analogs are recommended treatments, but they often have side effects and are not always effective. Ozone is an oxygen donor, an immunomodulator, an inducer of antioxidant enzymes and the endothelial nitric oxide synthase, a metabolic booster, and a stem cell activator. I report the case of a scleroderma patient treated effectively with autohemotherapy with ozone and a clear reduction of Raynaud's episodes and resolution of the edema of the hands. Furthermore, the capillaroscopic evaluation showed a rapid modification of the microcirculation which remained unchanged for months. Ozone therapy is effective to treat the Raynaud phenomenon and hand edema and should be considered, at least, as a complementary therapy to the standard of care, especially in patients who are unresponsive or with frequent adverse drug reactions. Further studies will be needed to confirm the efficacy of ozone therapy in scleroderma vasculopathy.