Rationale: Postconditioning (PostC) at the time of primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) may reduce infarct size and improve myocardial salvage. However, clinical trials have shown inconsistent benefit. Objective: We performed the first NHLBI-sponsored trial of PostC in the United States utilizing strict enrollment criteria to optimize the early benefits of PostC and assess its long-term effects on LV function. Methods and Results: We randomized 122 STEMI patients to PostC (Four, 30-sec. PTCA inflations / deflations) + PCI(n=65) vs. routine PCI (n=57). All subjects had an occluded major epicardial artery (TIMI= 0) with ischemic times between 1 and 6 hours with no evidence of preinfarction angina or collateral blood flow. Cardiac MRI measured at 2 days post-PCI showed no difference between the PostC group and Control in regards to infarct size (22.5 ± 14.5 g vs. 24.0 ± 18.5 g), myocardial salvage index (MSI) (30.3 ± 15.6% vs. 31.5 ± 23.6%) or mean LVEF. MRI at 12-months showed a significant recovery of LVEF in both groups (61.0 ± 11.4% and 61.4± 9.1%; p < 0.01). Subjects randomized to PostC experienced more favorable remodeling over 1 year (LVEDV = 157 ± 34 to 150 ± 38 ml) compared to the Control group (157 ± 40 to 165 ± 45 ml) (p < 0.03) and reduced microvascular obstruction (MVO) (p=0.05) on baseline MRI and significantly less adverse LV remodeling compared to Control subjects with MVO (p < 0.05). No significant adverse events were associated with the PostC protocol and all patients but one (hemorrhagic stroke) survived thru one-year of follow-up. Conclusions: We found no early benefit of PostC on infarct size, MSI and LV function compared to routine PCI. However, PostC was associated with improved LV remodeling at one year of follow-up, especially in subjects with MVO.