Preclinical and clinical studies have demonstrated that stem cell transplantation can improve the left ventricular (LV) contractile performance, yet the underlying mechanisms remain unknown. We examined whether mesenchymal stem cell (MSC) transplantation-induced beneficial effects are secondary to paracrine-associated improvements in LV contractile performance, wall stress, and myocardial bioenergetics in hearts with postinfarction LV remodeling. Myocardial contractile function and bioenergetics were compared 4 wk after acute myocardial infarction in normal pigs (n = 6), untreated pigs with myocardial infarction (MI group; n = 6), and pigs receiving autologous MSC transplantation (MI + MSC group; n = 5). A distal occlusion of the left anterior descending coronary artery instigated significant myocardial hypertrophy. Ejection fraction decreased from 55.3 +/- 3.1% (normal) to 30.4 +/- 2.3% (MI group; P < 0.01) and to 45.4 +/- 3.1% (MI + MSC group; P < 0.01 vs. MI). Hearts in the MI group developed severe contractile dyskinesis in the infarct zone and border zone (BZ). MSC transplantation significantly improved contractile performance from dyskinesis to active contraction (P < 0.01 vs. MI). BZ systolic wall stress was severely increased in MI hearts but significantly improved after MSC transplantation (P < 0.01 vs. MI). The BZ demonstrated profound bioenergetic abnormalities in MI pigs; this was significantly improved after MSC transplantation (P < 0.01 vs. MI). Patchy spared myocytes were found in the infarct zone of hearts receiving MSC transplantation but not in control hearts. These data demonstrate that MSC transplantation into the BZ causes significant improvements in myocardial contractile performance and reduction in wall stress, which ultimately results in significant bioenergetic improvements. Low cell engraftment indicates that MSCs did not provide a structural contribution to the damaged heart and that the observed beneficial effects likely resulted from paracrine repair mechanisms.