Low-response to the P2Y12 adenosine diphosphate (ADP)-receptor antagonist clopidogrel was suggested to correspond to a higher incidence of stent thrombosis (ST). This prospective observational study assessed the capability of two platelet function assays, e.g. direct measurement of the phosphorylation status of vasodilator-stimulated phosphoprotein (VASP) and ADP-induced platelet aggregation for definition of the individual risk to develop ST. Ninety-nine patients with an elevated high risk to develop ST were enrolled. All patients received a dual antiplatelet therapy consisting of 100 mg aspirin and 75 mg clopidogrel during an observation period of six months. Flow cytometry of VASP phosphorylation and densitometrically-determined measurement of ADP-induced platelet aggregation was performed 72-96 hours after stent implantation. These data were related to angiographically confirmed ST. Nine patients suffered from angiographically confirmed ST (9.1%). The meanVASP-platelet reactivity indices (VASP-PRI) and values for ADP-induced platelet aggregation in the ST group were significantly higher (60.8 +/- 13.0 and 60.9 +/- 13.1, respectively) compared to patients without ST (41.3 +/- 14.0 and 50.8 +/- 14.4, P < 0.001 vs. 0.048, respectively). There was a fair correlation between both methods using non-linear regression analysis (r = 0.332). In a multivariate analysis, VASP was the only independent predictor of ST and was superior to previously identified angiographic parameters. Receiver- operator characteristic (ROC) curve analysis revealed a cut-off value for VASP-PRI of <48% to be associated with low risk of ST. In conclusion, determination of VASP phosphorylation is superior to conventional platelet aggregometry and angiographic parameters for assessing the risk of ST. Patients with a VASP-PRI >48% seem to have a significantly increased risk.