Systemic mastocytosis (SM) may rarely be associated with lymphoproliferative disorders. In such cases, the relationship between the neoplastic mast cells and the malignant lymphocytes remains unclear. We describe a patient with indolent SM whose bone marrow showed evidence of low-grade B-cell lymphoma. By detecting the activating KIT mutation D816V in the microdissected bone marrow mast cells, but not in the neoplastic B-lymphocytes, we demonstrate the distinct clonal origins of the mastocytosis and lymphoma when these two entities coexist. We also highlight the clinical and pathologic differences between SM associated with lymphoid as opposed to myeloid neoplasms and discuss their pathogenesis.