Vascular endothelial growth factor (VEGF) and erythropoietin (EPO) have profound effects on the endothelium and endothelial progenitor cells (EPCs), which originate from the bone marrow and differentiate into endothelial cells. Both EPO and VEGF have demonstrated an ability to increase the number and performance properties of EPCs. EPC behavior is highly dependent on nitric oxide (NO), and both VEGF and EPO can stimulate intracellular NO. EPO can bind to the homodimeric EPO receptor (EPO-R) and the heterodimeric receptor, EPO-R and the common beta receptor (betaC-R). Although VEGF has several receptors, VEGF-R2 appears most critical to EPC function. We demonstrate that EPO induction of NO is dependent on the betaC-R and VEGF-R2, that VEGF induction of NO is dependent on the expression of the betaC-R, and that the betaC-R and VEGF-R2 interact. This is the first definitive functional and structural evidence of an interaction between the 2 receptors and has implications for the side effects of EPO.