Rationale <p>Although direct cardiac delivery of bone marrow-derived mesenchymal stromal cells (MSCs), c-kit–positive (c-kit^POS) cardiac progenitor cells (CPCs), and cardiac mesenchymal cells (CMCs) is beneficial in preclinical models of chronic ischemic cardiomyopathy (ICM), the optimal route of cell administration and the comparative efficacy of these cell types remain unclear. Addressing these issues is important to inform translational studies of heart failure (HF).</p> Objective <p>To directly compare the effects of 3 repeated intravenous infusions of syngeneic MSCs, CPCs, and CMCs in a well-established rat model of chronic ICM.</p> Methods and Results <p>Rats with a 30-day-old myocardial infarction (MI) received 3 repeated intravenous infusions, 35 days apart, of vehicle (Dulbecco’s phosphate-buffered saline [DPBS]), MSCs, CMCs, or CPCs, at a dose of 12 × 10⁶ cells. The left ventricular (LV) function was assessed by serial echocardiography and by hemodynamic studies at the end of the protocol. Results showed that all three types of cells improved LV function assessed by echocardiography, but only MSCs and CPCs improved hemodynamic indices of LV function. In the noninfarcted LV region, all three cell types reduced fibrosis, but only MSCs and CPCs reduced cardiomyocyte cross-sectional area and CD45 positive cell infiltration.</p> Conclusions <p>Three repeated intravenous infusions of allogeneic MSCs, CPCs, or CMCs improved echocardiographic measures of LV function and reduced myocardial fibrosis in rats with chronic MI. However, only MSCs and CPCs improved hemodynamic indices of LV function and reduced hypertrophy and inflammation in the viable, noninfarcted myocardium. These data confirm the effectiveness of intravenous cell delivery in alleviating ICM and suggest therapeutic superiority of MSCs and CPCs over CMCs.</p>