Previous studies have shown that more complete platelet inhibition improves the coronary flow reserve (CFR), a measure of microvascular integrity, in patients undergoing percutaneous coronary intervention (PCI). We hypothesized that patients with aspirin resistance would have impaired CFR after elective PCI. We used VerifyNow Aspirin to determine the response to aspirin in 117 consecutive patients who underwent elective single-lesion PCI. The assay results are expressed quantitatively in Aspirin Reaction Units based on the degree of platelet aggregation. All patients received a 300-mg loading dose of clopidogrel >12 hours before and a 75-mg maintenance dose the morning of PCI. CFR was estimated using the Thrombolysis In Myocardial Infarction frame count method. Of the 117 patients, 22 (18.8%) were aspirin resistant. The clinical, angiographic, and procedural characteristics of the aspirin-sensitive and -resistant patients were balanced. All patients underwent successful PCI with <50% residual diameter stenosis and Thrombolysis In Myocardial Infarction grade 3 flow after PCI. Aspirin-resistant patients had a lower CFR than the aspirin-sensitive patients (1.42 +/- 0.35 vs 1.80 +/- 0.64, p = 0.018). Univariate correlates of CFR included the Aspirin Reaction Unit (r = -0.227, p = 0.014) and post-PCI creatine kinase-MB elevation (p = 0.048). Multivariate linear regression analysis revealed the Aspirin Reaction Unit to be the only independent determinant of CFR after PCI (r2 = 0.051, p = 0.014). Thus, aspirin resistance was associated with impaired CFR in patients who underwent elective PCI, implicating insufficient aspirin-induced platelet inhibition as a cause of microvascular dysfunction by distal atherothrombotic embolization and/or spasm.