Background - Transplantation (Tx) of skeletal myoblasts (SM) within an infarcted myocardium improves global left ventricular (LV) function, although a direct systolic effect remains controversial. Methods and Results - Global and regional LV functions were studied in a sheep model (n = 16) of infarction before (baseline), and 4 (M4), and 12 (M12) months after in-scar injections of autologous SM or culture medium (CM). LV end-diastolic volume (EDV), ejection fraction (EF), wall motion score (WMS), and systolic myocardial velocity gradient (MVG) across the scar were measured by echocardiography with tissue Doppler imaging. Parameters were similar at baseline between groups. At M4, Tx of SM reduced the postinfarction increase in EDV (72±8 versus 105±13 mL in the CM group, P<0.05) and the decrease in EF (48±5 versus 33±3% in the CM group, P=0.006) although it improved WMS (5.4±1.2 versus 13±2.2 in the CM group, P<0.01) and SMVG (0.60±0.13 versus -0.04±.13 seconds-1 in the CM group, P<0.05). Results were similar at M12. In-scar accumulation of myotubes and SM were detected in all Tx animals up to M12, with co-expression of fast and slow isoforms of the myosin heavy chain (MHC) (30% of the fibers versus 0% in the normal skeletal muscle) and decreased collagen density (30±2% versus 73±3%, P<0.0001). Conclusion - For up to 1 year, Tx of SM limits postinfarction EF deterioration and improves systolic scar function through colonization of fibrosis by skeletal muscle cells with expression of both MHC isoforms, which may confer to the graft the ability to withstand a cardiac-type workload.