Cell therapy is a promising treatment modality to improve heart function in acute myocardial infarction. However, the mechanisms of action and the most suitable cell type have not been finally determined. We performed a study to compare the effects of mesenchymal stem cells (MSCs) harvested from different tissues on LV function and explore their effects on tissue structure by morphometry and histological staining for species and lineage relationship. MSCs from skeletal muscle (SM-MSCs) and adipose tissue (ADSCs) were injected in the myocardium of nude rats 1 week after myocardial infarction. After 4 weeks of observation, LVEF was significantly improved in the SM-MSCs group (39.1%) and in the ADSC group (39.6%), compared to the placebo group (31.0%, p < 0.001 for difference in change between groups). Infarct size was smaller after cell therapy (16.3% for SM-MSCs, 15.8% for ADSCs vs. 26.0% for placebo, p < 0.001), and the amount of highly vascularized granulation tissue in the border zone was significantly increased in both groups receiving MSCs (18.3% for SM-MSCs, 22.6% for ADSCs vs. 13.1% for placebo, p = 0.001). By in situ hybridization, moderate engraftment of transplanted cells was found, but no transdifferentiation to cardiomyocytes, endothelial cells, or smooth muscle cells was observed. We conclude that MSC injections lead to improved LVEF after AMI in rats predominantly by reduction of infarct size. After 4 weeks, we observed modulation of scar formation with significant increase in granulation tissue. Transdifferentiation of MSCs to cardiomyocytes or vascular cells did not contribute significantly in this process. MSCs from skeletal muscle and adipose tissue had similar effects.