Erythropoietin (EPO) is a well-recognized hormone that induces erythrocytosis in a wide range of physiologic and pathologic situations in mammals. One of these situations is a paraneoplastic erythrocytosis, which might be seen in association with various neoplasms, including renal cell carcinoma (RCC), hepatoma, and cerebellar hemangioblastoma. Although there have been multiple studies confirming the association between this erythrocytosis and the production of EPO by tumor cells, immunohistochemical detection of EPO in formalin-fixed, paraffin-embedded tissue was not described. We report on the use of microwave antigen retrieval to detect EPO in RCCs in such routinely processed tissues. We selected 19 RCCs received as nephrectomy specimens, fixed in formalin, and routinely processed. These cases were previously diagnosed on the basis of morphologic, immunohistochemical, and clinical features. We examined the immunoreactivity of these specimens with a monoclonal anti-EPO antibody. Fetal (20 wk gestational age) liver served as a positive control. Intense positive immunoreactivity was observed as cytoplasmic, granular staining in fetal hepatocytes. Fourteen RCCs (10 clear cell and 4 tubulopapillary types) demonstrated unequivocal cytoplasmic immunoreactivity. Additionally, two clear cell tumors were only focally positive, whereas three (16%) were negative. EPO immunoreactivity might thus prove to be of value in the diagnosis or confirmation of RCC, particularly in the context of routinely processed material.