Reactive hemophagocytic syndrome (RHS) is an uncommon life-threatening disorder. It is believed to be caused by widespread non-neoplastic proliferation and inappropriate activation of mature macrophages, resulting in excessive cytokine activation which leads to hematophagocytosis by cells of the macrophage-monocyte lineage and multiorgan dysfunction. RHS may be associated with infections caused by bacterial, viral and fungal organisms as well as lymphoproliferative disorders, nonhematopoietic malignancies, autoimmune diseases and some therapeutic drugs. Immunosuppression is a frequent underlying condition in RHS. The following case presentation describes a patient with a history of chronic hepatitis C, cryoglobulinemia, renal failure and Staphylococcus aureus perinephric abscess and bacteremia, who, at autopsy, was found to have disseminated histoplasmosis with fungal endocarditis and RHS.