We examined the cardiac effects of chronic erythropoietin (EPO) therapy initiated 7 days after myocardial infarction (MI) in rats. A single high dose of EPO has been shown to reduce infarct size by preventing apoptosis when injected immediately after myocardial ischemia. The proangiogenic potential of EPO has also been reported, but the effects of chronic treatment with standard doses after MI are unknown. In this study, rats underwent coronary occlusion followed by reperfusion or a sham procedure. Infarcted rats were assigned to one of three treatment groups: 1) 0.75 microg/kg darbepoetin (MI+darb 0.75, n = 12); 2) 1.5 microg/kg darbepoetin (MI+darb 1.5, n = 12); 3) vehicle (MI+PBS, n = 16), once a week from day 7 postsurgery. Sham rats received the vehicle alone (n = 10). After 8 wk of treatment, the animals underwent echocardiography, left ventricular pressure-volume measurements, and peripheral blood endothelial progenitor cell (EPC) counting. MI size and capillary density in the border zone and the area at risk (AAR) were measured postmortem. The AAR was similar in the three MI groups. Compared with MI+PBS, the MI+darb 1.5 group showed a reduction in the MI-to-AAR ratio (20.8% vs. 38.7%; P < 0.05), as well as significantly reduced left ventricle dilatation and improved cardiac function. This reduction in post-MI remodeling was accompanied by increased capillary density (P < 0.05) and by a higher number of EPC (P < 0.05). Both darbepoetin doses increased the hematocrit, whereas MI+darb 0.75 did not increase EPC numbers or capillary density and had no functional effect. We found that chronic EPO treatment reduces MI size and improves cardiac function only at a dose that induces EPC mobilization in blood and that increases capillary density in the infarct border zone.