Hemophagocytosis (HP), a feature seen in malignant histiocytosis and infection- and lymphoma-associated disorders, has not been previously emphasized in Erdheim-Chester disease (ECD). Generally, ECD is recognized as a rare, systemic, non-Langerhans cell histiocytosis with a variable clinical course. Herein, we describe a unique case of multisystem non-Langerhans cell histiocytic proliferation with a fulminant clinical course (death occurred within 3 months of presentation) that showed prominent HP and extensive involvement of multiple organs, including the lungs, resulting in respiratory failure. Hemophagocytosis led to severe anemia that required transfusion and thrombocytopenia. Antemortem lung and bone marrow biopsy specimens revealed involvement by a histiocytic infiltrate with features highly suggestive of ECD and HP. Furthermore, the autopsy documented the presence of HP and the histiocytic infiltrate in multiple other organs. This case is best categorized as a variant form of ECD. Recognizing this variant has the following important implications: (1) HP may be a marker for fulminant clinical course in ECD, (2) the presence of HP does not exclude a diagnosis of ECD, and (3) ECD should be considered in the differential diagnosis of HP.