Objectives The present study was designed as a face-to-face functional comparison of human skeletal myoblasts (SMs) and CD133 + bone marrow-derived hematopoietic progenitors in an animal model of semichronic myocardial infarction. Background Compared with SMs, bone marrow-derived cells have the advantage of plasticity and might more effectively regenerate ischemic cardiac tissue. However, few data exist on the comparative efficacy of these two cell types in semichronic infarcts. Methods A myocardial infarction was created by coronary ligation in 32 nude rats. Ten days later, rats received in-scar injections of human SMs, CD133 + progenitors, or culture medium. Left ventricular function was assessed before and one month after transplantation by echocardiography and pressure-volume loops. Immunofluorescence, polymerase chain reaction, and in situ hybridization were used to detect cells grafted in the hearts. Results One month after transplantation, left ventricular ejection fraction decreased by 8 ± 4% in controls, whereas it increased by 7 ± 3% in CD133 +-grafted hearts (p = 0.0015 vs. controls) and further by 15 ± 5% in SM-treated hearts (p = 0.008 vs. controls). Systolic indices yielded by pressure-volume loops paralleled these data. Engrafted myotubes were identified in all SM-treated hearts by immunofluorescence, whereas in CD133 +-grafted hearts, few human cells were only detected by polymerase chain reaction. Conclusions In the setting of postinfarction scars, the transplantation of bone marrow-derived CD133 + progenitors improves cardiac function, but this benefit is not superior to that afforded by myogenic cells. © 2004 American College of Cardiology Foundation.