Aims To assess the short- and long-term effects of postconditioning (p-cond) on infarct size, extent of myocardial salvage, and left ventricular ejection fraction (LVEF) in a series of patients presenting with evolving ST-elevation myocardial infarction (STEMI). Previous studies have shown that p-cond during primary percutaneous coronary intervention (PCI) confers protection against ischaemia-reperfusion injury and thus might reduce myocardial infarct size. Methods and results Seventy-nine patients undergoing PCI for a first STEMI with TIMI grade flow 0-1 and no collaterals were randomized to p-cond (n= 39) or controls (n= 40). Postconditioning was performed by applying four consecutive cycles of 1 min balloon inflation, each followed by 1 min deflation. Infarct size, myocardial salvage, and LVEF were assessed by cardiac-MRI 1 week and 6 months after MI. Postconditioning was associated with lower myocardial salvage (4.1 ± 7.2 vs. 9.1 ± 5.8% in controls; P= 0.004) and lower myocardial salvage index (18.9 ± 27.4 vs. 30.9 ± 20.5% in controls; P= 0.038). No significant differences in infarct size and LVEF were found between the groups at 1 week and 6 months after MI. Conclusion This randomized study suggests that p-cond during primary PCI does not reduce infarct size or improve myocardial function recovery at both short- and long-term follow-up and might have a potential harmful effect.