© 2015 The Authors. Background: Pre-clinical studies have shown that hypoxia preconditioning can enhance stem cell therapeutic potential for myocardial repair. We sought to investigate the safety and feasibility of intracoronary administration of hypoxia-preconditioned bone marrow mononuclear cells (HP-BMCs) for acute ST segment elevation myocar-dial infarction (STEMI). Methods: We randomized 22 patients with acute STEMI to receive intracoronary administration of normoxia bone marrow mononuclear cells (N-BMCs) (n = 11) or HP-BMCs (n = 11) following successful reperfusion. Another 14 patients receiving standard therapy were recruited as control (n = 14). Results: There werenodifferences inthe occurrence of major adverse cardiovascular events at 30 days and 1 year among three groups. There were significant improvement in the change of left ventricular end-diastolic volume (LVEDV) and end-systolic volume (LVESV) in HP-BMC group both at6 and 12 months compared with N-BMCs or control group (P < 0.05). No differences were observed in the change of left ventricular ejection fraction (LVEF), or wall motion score index (WMSI) among three groups. Nevertheless, WMSI was improved in HP-BMCs and N-BMC group (P < 0.05, within group), but not in control. The ratio of myocardial perfusion defect determined by SPECT was significantly decreased in HP-BMCs and N-BMC groups at 6 months compared with baseline (P < 0.05, within group), but no significant differences were observed among three groups. Conclusions: Our results provide the first-in-man evidence that intracoronary administration of HP-BMCs following acute MI appears to be safe and feasible. These results provide the basis for future prospective randomized clinical trials in a larger patient cohort.