Hemolytic anemia in the setting of malignancy is a rare manifestation of paraneoplastic syndrome with significant morbidity. Here we discuss a case involving metastatic breast cancer presenting with severe hemolytic anemia and renal failure secondary to thrombotic microangiopathy of malignancy. This case discusses the workup for secondary hemolytic anemia, a possible role for therapeutic plasma exchange in this setting, as well the current understanding of the management of microangiopathic hemolytic anemia of malignancy.