Objective: To evaluate the possible role of high on-aspirin platelet reactivity (HaPR) in a prospective cohort of acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). Background: Several studies documented that high on-clopidogrel platelet reactivity (HcPR) is associated with increased risk of ischemic events in ACS patients undergoing PCI. On the contrary, conflicting data are available on HaPR and clinical outcome. Methods: Platelet reactivity was assessed by light transmittance aggregometry using arachidonic acid as an agonist in 1789 ACS patients undergoing PCI. Results: HaPR was found in 20.3% of patients. These patients were significantly older, with a higher prevalence of hypertension, diabetes and reduced ejection fraction. Patients with non ST-segment elevation ACS, 3-vessel disease and multivessel PCI had a significantly higher prevalence of HaPR. In addition, stent number and length, and use of drug-eluting stents were significantly higher in HaPR patients. At 24-month follow-up the prevalence of cardiac death was 9.7% in HaPR and 3.8% in non-HaPR [HR2.63(1.72-4.02), p <. 0.0001], that of stent thrombosis 6.1% in HaPR and 2.6% in non-HaPR [HR2.4(1.42-4.07), p <. 0.001], with no significant differences in other clinical end-points. At multivariate analysis, HaPR was confirmed as an independent risk factor for cardiac death [HR1.88(1.21-2.93), p = 0.005] and stent thrombosis [HR1.91(1.12-3.28), p = 0.018]. The addition of HaPR to a model including clinical and procedural risk factors and HcPR led to a significant improvement in the prediction of cardiac death (NRI 39. ±. 10%, p = 0.0003) and stent thrombosis (NRI 34.7. ±. 13.2%, p = 0.009). Conclusion: HaPR was found to be an independent risk factor for cardiac death and stent thrombosis in ACS patients undergoing PCI.