Histiocytosis X (HX) is a rare disorder of histiocytic proliferation characterized by a broad spectrum of clinicopathologic disease. An unusual case of Letterer-Siwe disease (LSD) or subacute disseminated HX in a 71-year-old woman is presented. The patient had a 3-year history of splenomegaly before skin lesions developed. She presented to our clinic at 1.5 years later and the diagnosis of HX was made by skin biopsy. Topical nitrogen mustard (NM) therapy resulted in complete clearing of cutaneous lesions. Her condition was stable over the next 10 months. However, she subsequently suffered a rapid and fatal dissemination of her disease. Systemic treatment with prednisone, vinblastine sulphate, and suppressin A (SA) (a calf thymus derived hormone preparation that specifically induces suppressor T-cells) was ineffective. Characteristic histopathologic, immunohistochemical, and electron microscopic findings of HX are illustrated. A review of the adult cases of LSD and treatment options for HX are presented and discussed.