Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) are both exceedingly rare histiocytic proliferations that can involve the skeletal system. We report on a case of ECD with some features suggestive of LCH. Radiographs demonstrated a large lytic lesion in the left femur, with multiple lesions of sclerosis involving both distal femurs and tibias. Both the lytic lesion and a sclerotic lesion were biopsied and demonstrated distinctive histologic features characteristic of ECD in the tibia and features of LCH in the femur. The clinical/radiologic and pathologic features that distinguish ECD and LCH as distinct entities are reviewed, and the underlying biological connection between them is discussed.