Systemic mast cell disease (SMCD) is an uncommon disorder characterized by a proliferation of mast cells involving the bone marrow, spleen, liver, skin, and lymph nodes. Although rare, the association of SMCD and other hematologic disorders is well established. To our knowledge, however, no previously published reports have described SMCD associated with the hypereosinophilic syndrome (HES). Herein we describe two patients who had SMCD in association with HES. Both patients had evidence of cardiac eosinophilic involvement, and both responded to systemic therapy. SMCD is often associated with eosinophilia and may be associated with HES more frequently than is commonly appreciated. Because congestive heart failure is a major cause of morbidity in patients with HES, cardiac assessment in patients with eosinophilia and SMCD is important in order to identify those with eosinophilic organ involvement and treat them aggressively.