Erdheim-Chester disease is a rare systemic disorder characterized by a fibrosing xanthogranulomatous infiltration of multiple organs. We report a case of Erdheim-Chester disease with diffuse necrosis leading to difficulty in making a prompt diagnosis. Radiologically, osteosclerotic lesions with osteolytic element involved metadiaphyses of both proximal tibia, and retroperitoneal infiltrations encasing both kidneys, both adrenals, and aorta were found. A biopsy of the tibia showed diffuse infiltration of foamy histiocytes, Touton-type giant cells, and fibroblastic cells associated with extensive coagulative necrosis. Immunohistochemically, foamy histiocytes were positive for CD68 and peanut agglutinin and negative for S-100 protein. A few Langerhans' cells, which were difficult to identify in hematoxylin-eosin stain, were highlighted by immunostain for S-100 protein. The patient received supportive therapy and was alive 1 1/2 years after diagnosis, with newly developed bilateral retrobulbar lesions and worsened heart failure.