The etiology of Langerhans cell histiocytosis (LCH), a mix between immune dysregulation, inflammation, and malignancy, remains unclear.1; 2; 3 ; 4 In half of the patients, an oncogenic BRAF mutation is found. 3 Because of the diversity of symptoms, the diagnosis of LCH, as defined by the Histiocyte Society, is often made with considerable delay. Multisystemic LCH, affecting 2 or more organ systems and “risk organs,” like the hematopoietic system, the spleen, liver, and central nervous system, implies a worse prognosis. 1; 3; 4; 5 ; 6 To raise the awareness of multisystemic LCH, the case of an elderly patient is presented and a new therapeutic scheme with pioglitazone (peroxisome proliferator–activated receptor-γ [PPAR-γ] agonist), etoricoxib (COX-2 inhibitor), and trofosfamide (alkylating medium) is described.