Spontaneous tumor lysis syndrome is an exceedingly rare manifestation of metastatic prostate cancer. It can masquerade as thrombotic thrombocytopenic purpura (TTP) or complement-mediated hemolytic uremic syndrome (HUS). These entities present with microangiopathic hemolytic anemia, thrombocytopenia, and renal failure, and improve with the initiation of plasma exchange and steroids. In situations where the laboratory data does not wholly validate the presumed diagnosis and clinical and laboratory deterioration occurs in spite of appropriate treatment, it is necessary to expand the differential diagnosis and investigation. In this case, worsening renal function, cytopenias, lactate dehydrogenase, and uric acid in the setting of proper treatment for TTP and complement-mediated HUS prompted additional analysis. This workup revealed bone marrow infiltration by metastatic prostate cancer complicated by tumor lysis syndrome.