We present a case of hemophagocytosis in the setting of a disseminated Histoplasma infection in a patient with B-cell chronic lymphocytic leukemia (CLL). A 68-year-old man with CLL presented with progressive pancytopenia and fevers after therapy with cyclophosphamide and fludarabine phosphate. Extensive evaluation for a source of infection revealed a pulmonary nodule. A biopsy specimen taken from the nodule showed granulomas containing Histoplasma organisms. A bone marrow biopsy specimen demonstrated disseminated histoplasmosis and intense hemophagocytosis. Antifungal therapy with amphotericin B was initiated, and the fevers and cytopenias resolved. Hemophagocytic syndrome is an uncommon condition with many origins. It is characterized by a proliferation of histiocytes with phagocytosis of formed elements of blood. Clinical manifestations include signs and symptoms of immune activation and decreased peripheral blood cell counts. This condition is often underdiagnosed because clinicians are unfamiliar with it.