AIMS: Bone marrow (BM) stem cells improve cardiac function and outcome after acute ST-segment elevation myocardial infarction (MI). In this randomized controlled trial, the effects of intracoronary transfer of autologous BM cells on left ventricular ejection fraction (LVEF) and volumes (2D-echo and resting SPECT), stroke volume [impedance cardiography (ICG)], autonomic control [heart rate variability (HRV)], baroreflex sensitivity (BRS), and exercise tolerance (cardiopulmonary exercise test) were assessed in post-MI patients. Exercise stress SPECT was also performed. METHODS AND RESULTS: After percutaneous coronary intervention (PCI), 38 patients with residual LV dysfunction were randomized to either the BM group (optimized treatment plus intracoronary transfer of autologous BM cells 4 + or - 1 days after PCI, n = 19) or control (C) group (optimized treatment only, n = 19). After 12 months, mean LVEF (%) increased 13.1 + or - 1.9 in the BM patients vs. 5.3 + or - 2.0 in C, with an increase in stroke volume (mL, 14.5 + or - 4.0 in BM vs. 1.8 + or - 3.7 in C) associated with improved HRV [SD (ms) 62.4 + or - 8.3 in BM vs. 19.0 + or - 7.5 in C), higher BRS (ms/mmHg, 8.0 + or - 1.8 in BM vs. -1.9 + or - 1.7 in C), and peak VO(2) (mL/kg min(-1), 3.5 + or - 1.0 in BM vs. -0.4 + or - 0.5 in C). Stress SPECT showed improvements in perfusion, regional and global LV function scores (P < 0.05 BM vs. C groups for all comparisons). Cell transfer did not increase the risk of adverse clinical, in-stent restenosis, or proarrhythmic events. CONCLUSION: The beneficial effect of autologous BM cells in post-MI patients with depressed LV function may be mediated by restoration of autonomic control, and improved exercise tolerance.