Pheochromocytoma is a neuroendocrine tumor associated with a variety of genetic disorders, which include von Hippel-Lindau disease (VHL) (1), multiple endocrine neoplasia type 2 (MEN 2), neurofibromatosis type 1 (NF 1), hereditary paraganglioma, and succinate dehydrogenase (SDHD) gene related tumors. Previous studies of VHL-associated and MEN 2-associated pheochromocytomas suggest morphological, biochemical, and clinical differences exist between the tumors, but the process by which they develop remains unclear. Studies in other VHL-associated tumors suggest that VHL gene deficiency causes co-expression of erythropoietin (Epo) and its receptor (Epo-R), which facilitates tumor growth. The objective of this study was to understand the different process of tumorigenesis for VHL and MEN 2-associated pheochromocytomas. Ten pheochromocytomas, (VHL patients n = 5, MEN 2 patients n = 5), were examined for the presence or absence of Epo and Epo-R using Western blot, immunohistochemistry, and RT-PCR analyses. Co-expression of Epo and Epo-R was found in all 5 VHL-associated pheochromocytomas; in contrast, expression of Epo-R, but not Epo, was documented in all 5 MEN 2-associated pheochromocytomas. Expression of Epo appears to be a result of VHL gene deficiency, possibly through activation of the hypoxia inducible factor-1 (HIF-1) pathway, whereas Epo-R is an embryonal marker whose sustained expression in both VHL and MEN 2-associated pheochomocytomas reflects an arrest or defect in development. These findings suggest an alternative process of tumorigenesis in VHL and MEN 2-associated pheochromocytomas and implicate Epo as a clinical biomarker to differentiate these tumors.