In this study, the effect of human erythropoietin Delta (Epo) on smooth muscle cell (SMC)-rich lesions was evaluated. Mice, of which the left carotid artery was ligated, were treated with suberythropoietic as well as erythropoietic doses of Epo and both doses of Epo enhanced SMC-rich lesion formation. No association was observed between hemoglobin levels and lesion size. Moreover, endothelial progenitor cell (EPC) numbers in the peripheral blood increased only in the erythropoietic dosing group, indicating that EPC numbers did not correlate with lesion size. Immunohistochemical analysis revealed that Epo-mediated enhancement of lesion formation correlates with increased signal transducer and activator of transcription 5 (Stat5) phosphorylation in the vessel wall. Experiments performed in cultured vascular cells demonstrated that Epo robustly induced phosphorylation of Stat5 in human umbilical vein endothelial cells (HUVECs), but only very weakly in SMCs. In tumor necrosis factor-alpha (TNFalpha)-activated HUVECS, Epo induced expression of platelet-derived growth factor B (PDGF-B), which was at least partially responsible for the induction of Stat5 phosphorylation in SMCs by HUVEC-conditioned medium. In conclusion, in mice Epo accelerates SMC-rich neointima formation, which correlates with increased Stat5 phosphorylation in the vessel wall but is independent of erythrocyte and EPC numbers.