The aims of the present study were: 1) to verify the tolerability of long-term, low-dose treatment of patients affected by systemic sclerosis with cyclosporin A; 2) to analyze the clinical outcome of treated patients in relationship to skin, esophageal, lung, kidney and microvascular organ involvement. Nine patients affected by diffuse systemic sclerosis were treated for periods ranging from 3 to 5 years with cyclosporin A at a dosage of 2.5 mg/kg/day. Cyclosporin A treatment was variably associated or not with treatments for Raynaud's phenomenon (pentoxiphylline, defibrotide, low-dose heparin, prostacyclin analogues) in relationship to the needs of single patients. We report on patient clinical evaluations performed every year and including plicometry, esophageal pH-manometry, pulmonary spirometry, renal duplex Doppler sonography, echocardiography as well as nailfold videocapillaroscopy. The results of single tests were converted into scores. The existence of statistically significant differences between baseline mean scores and mean scores after 1, 2 and 3 years of therapy was analyzed. All patients tolerated cyclosporin A well, and no definitive withdrawals from the study were observed. Hypertricosis appeared in 3 patients, and 1 patient interrupted treatment for 6 months because of the onset of pneumonitis. No alterations of blood pressure and renal functionality were detected. Statistically significant reduction of all analyzed mean scores was observed after 2 and/or 3 years of cyclosporin A treatment with respect to baseline. The overall results suggest an encouraging clinical effect for low-dose, long-term cyclosporin A treatment in systemic sclerosis. Satisfactory tolerability and clinical improvement were observed in all the patients consecutively treated for at least 3 years.