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Background: A cell combination of human mesenchymal stem cells (MSCs) and c-kit+ cardiac stem cells (CSCs) improves left ventricular (LV) performance to a greater degree than MSCs alone in post myocardial infarction swine. To advance the development of cell combination therapy, we administered autologous swine cells, and tested the hypothesis that transendocardial autologous CSCs/MSCs produces greater improvement of performance than MSCs in a rigorous model of heart failure due to post infarct LV remodeling.Methods: Gottingen mini-swine (n=28) underwent LAD coronary artery occlusion followed by reperfusion, and allowed to undergo LV remodeling for 90 days. Autologous MSCs were amplified from bone marrow and CSCs from right ventricular biopsies in each swine, and injections of either CSC/MSC combo (1M/200M, n=7), MSCs (200M, n=7), or placebo (Plasmalyte, n=6) were injected to the infarct-border zone via the NOGA system. Cardiac MRI and pressure volume loops were obtained before and after therapy.Results: Both cell groups had substantially reduced scar size (Combo –37.2.9± 5.4% vs MSCs –38.8±7.5% vs placebo −7.2±6.3, P=0.0001) and increased viable tissue (Combo +30.9±7% vs MSCs +41.8±10.5% vs placebo +7.7±4.5, P<0.0001) relative to placebo. Ejection Fraction (EF) improved only in the Combo group (Combo +7.0±2.8 vs MSCs +3.4±1.3 vs placebo +1.2±1.6 EF units, P=0.04). Accompanying this EF restoration was a substantial improvement in the Combo group in stroke volume (Combo +47.2±11.1% vs MSCs +32.6±12.0% vs placebo +10.8±4.5, P<0.0001), cardiac output (Combo +35.9±7.6% vs MSCs 41.9±26.5% vs placebo −16.4±6.6%, P=0.01) and diastolic strain rate (Combo +18.9±8.6% vs MSCs 14.0±8.8% vs placebo −14.9±9.5%, P=0.03).Conclusions: Combination cell therapy and MSCs alone dramatically reduce scar size in a swine model of chronic ischemic cardiomyopathy. In contrast, combination therapy has much greater impact on functional recovery, increasing EF to [near normal] levels. These findings illustrate that interactions between ckit+ CSCs and MSCs result in substantial enhancement in cardiac performance, establish the safety of autologous cell combination strategies, and support the development of an advanced second generation cell therapeutic product.