In anemic patients with heart failure (HF), erythropoietin type drugs can elicit clinical improvement. This study examined the effects of chronic monotherapy with darbepoetin alfa (DARB) on LV function and remodeling in non-anemic dogs with advanced HF. HF (LV ejection fraction, EF ~25%) was produced in 14 dogs by intracoronary microembolizations. Dogs were randomized to once a week subcutaneous injection of DARB (1.0 µg/kg, n=7) or to no therapy (HF, n=7). All the procedures were performed during cardiac catheterization under general anesthesia and sterile conditions. LV end diastolic (EDV) and end-systolic volumes (ESV) and EF were measured before initiating therapy and at the end of 3 months of therapy. mRNA and protein expression of caspase-3, hypoxia inducible factor-1 alfa (HIF-1) and bone marrow-derived stem cell (BMSC) marker c-Kit were determined in LV tissue. In HF dogs, EDV and ESV increased and EF decreased after 3 months of follow-up. Treatment with DARB prevented the increase in EDV, decreased ESV and increased EF. DARB therapy also normalized the expression of HIF-1 and active caspase-3 and enhanced the expression of c-Kit. We conclude that chronic monotherapy with DARB prevents progressive LV dysfunction and dilation in non-anemic dogs with advanced HF. These results suggest that DARB elicits beneficial effects in HF that are independent of the presence of anemia.