Systemic sclerosis (SSc) is a multisystem connective disorder in which endothelial damage leads to fibrotic reactions through platelet hyperaggregability and inappropriate release of platelet-derived growth factors. With other colleagues, I have previously reported that melatonin seems to have a direct favorable effect on endothelium (stopping of bleeding symptoms in thrombocytopenic patients). Furthermore, melatonin has been described as performing an antiaggregating activity, and ACTH and vitamin E have been described as increasing melatonin effects. This provided the rationale to treat 5 SSc patients with melatonin plus ACTH and vitamin E. Patients received the treatment for 1 month. The therapy was continued for 2 additional months in patients with stable or responding disease. After 3 months, the stable or responding patients continued the therapy for 2 months and longer. All patients had a partial response after 1 month. Continuing with the treatment, none of the 5 patients had disease progression (average follow-up time of 16.6 months; range, 7-44 months). Toxicity was lacking, with the only side effect being drowsiness. Our experience suggests that the combination of melatonin-ACTH-vitamin E may be safe and effective in patients with SSc.