Abstract Background Cellular transplantation has emerged as a novel therapeutic option for treatment of ventricular dysfunction. Both skeletal myoblasts (SM) and mesenchymal stem cells (MSC) have been proposed as ideal cell for this aim. The aim of this study is to compare the efficacy of these cells in improving ventricular function and to evaluate the different histological findings in a rat model of severe post-infarct ventricular dysfunction. Methods Myocardial infarction was induced in Wistar rats by left coronary occlusion. Animals with resulting ejection fraction (EF) lower than 40% were included. Heterologous SM were obtained by lower limb muscle biopsy and MSC by bone marrow aspiration. Nine days after infarction, rats received intramyocardial injection of SM ( n = 8), MSC ( n = 8) or culture medium, as control ( n = 11). Echocardiographic evaluation was performed at baseline and after 1 month. Histological evaluation was performed after HE and Gomori's trichrome staining and immunostainig against desmin, fast myosin and factor VIII. Results There was no difference in baseline EF and left ventricular end diastolic (LVEDV) and systolic volume (LVESV) between all groups. After 1 month a decrease was observed in the EF in the control group (27.0 ± 7.10% to 21.46 ± 5.96%, p = 0.005) while the EF markedly improved in SM group (22.66 ± 7.29% to 29.40 ± 7.01%, p = 0.04) and remained unchanged in the MSC group (23.88 ± 8.44% to 23.63 ± 10.28%, p = 0.94). Histopathology identified new muscular fibers in the group that received SM and new vessels and endothelial cells in the MSC. Conclusion Skeletal myoblasts transplantation resulted in myogenesis and improvement of ventricular function. In contrast, treatment with mesenchymal stem cells resulted in neoangiogenesis and no functional effect.