The treatment of patients who suffer from a disseminated form of Langerhans cell histiocytosis (LCH) is still controversial. So far, few larger randomized studies have been performed. The authors present 3 patients with a disseminated form of LCH--4 months, 9 months, and 2 years old, respectively. The lesional Langerhans cells in each patient showed positive immunohistochemical reaction to S-100 protein and the presence of Birbeck granules was confirmed by electron microscopy. All the patients were treated with etoposide (VP-16), 200 mg/m2 for 3 consecutive days, with 15 cycles at intervals of 3 weeks between each cycle, followed by maintenance therapy with IFN-alpha. All 3 patients reached complete stabile remission. The patients were young, at high risk, with multiple-organ involvement of LCH, and two of them had obvious signs of organ dysfunction at presentation, suggesting a poor prognosis. All remain disease-free several years after therapy. The results suggest that INF-alpha may prevent recurrences in high-risk patients.