Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor receptor superfamily, has recently been linked to atherosclerosis and development of postinfarction heart failure. This study was designed to assess the association between admission OPG levels and microvascular obstruction (MVO) in patients who underwent primary percutaneous coronary intervention (p-PCI). Plasma samples for OPG analysis were obtained <30 minutes after admission in 47 patients who underwent p-PCI. Angiographic no-reflow (Thrombolysis In Myocardial Infarction [TIMI] flow grade <3 or 3 with myocardial blush grade 0 or 1 after p-PCI) was assessed immediately after p-PCI. MVO was assessed and quantified by the intracoronary hemodynamic measure of index of microcirculatory resistance performed on day 4 or 5 after p-PCI. Patients with angiographic no-reflow had significantly higher OPG levels on admission. On multiple linear regression analysis, OPG (β = 0.412, p = 0.001) and B-type natriuretic peptide (β = 0.409, p = 0.001) levels were independently and directly associated with the index of microcirculatory resistance. In conclusion, plasma OPG levels on admission are strongly associated with MVO and significantly correlated with the degree of MVO after p-PCI. It remains to be established whether improvement of microvascular perfusion is feasible with therapeutic strategies aimed to decrease circulating OPG levels.