The effect of periprocedural platelet reactivity and clinical outcomes in diabetic patients taking clopidogrel and undergoing percutaneous coronary intervention (PCI) is unclear. The aim of the present study was to prospectively evaluate the influence of diabetes mellitus (DM) on platelet reactivity measured by the VerifyNow P2Y12 assay and on periprocedural outcomes in patients receiving clopidogrel and undergoing PCI. A total of 285 consecutive clopidogrel-treated patients undergoing elective PCI were included. Platelet function analysis was performed using the VerifyNow P2Y12 assay. High platelet reactivity (HPR) after clopidogrel was defined as a platelet reaction unit value > or =240. Cardiac biomarkers were measured before and 8 and 24 hours after intervention. Patients with DM had significantly higher platelet reactivity before PCI compared to nondiabetics (214 +/- 83 vs 193 +/- 68 platelet reaction units, p = 0.02). HPR was more frequently observed in diabetics (36% vs 22%, p = 0.01) before PCI. Patients with DM had an increased incidence of periprocedural myocardial infarction (MI; 11% vs 4%, p = 0.04). When the entire population was divided by the presence or absence of DM and HPR, patients with DM and HPR presented the highest incidence of periprocedural MI (p for trend = 0.0008). HPR was an independent predictor of periprocedural MI (odds ratio 8.34, 95% confidence interval 2.60 to 26.76, p = 0.0003). In conclusion, patients with DM undergoing PCI have higher platelet reactivity at the time of PCI despite adequate clopidogrel pretreatment and subsequently worse periprocedural outcomes. Point-of-care platelet function testing may help to identify patients at higher risk of periprocedural MI.