To compare the effect of two Proton Pomp Inhibitors (PPI) on platelet response to clopidogrel after coronary stenting for Non ST Elevation Acute Coronary Syndrome (NSTE ACS). Use of omeprazole has been reported to decrease significantly the clopidogrel antiplatelet effect because of cytochrome P450 interaction. As all PPIs are metabolized by CYP2C19, but to a varying degree, we hypothesized that the reported negative omeprazole-clopidogrel drug interaction may not be due to a class effect. 104 patients undergoing coronary stenting for NSTE ACS were prospectively included and randomized to omeprazole or pantoprazole 20 mg. They received at discharge 75 mg aspirin and 150 mg clopidogrel. Platelet reactivity index VASP was used to assess clopidogrel response and ADP-induced aggregation for platelet reactivity (ADP-Ag). After one month, patients receiving pantoprazole had a significantly better platelet response to clopidogrel as assessed with the PRI VASP: 36±20% vs 48±17%, p=0.007. We identified more clopidogrel non responders in the omeprazole group than in the pantoprazole group: 44% vs 23%, p=0.04, OR 2.6 [1.2-6.2]. Conversely, we did not observe any significant difference in platelet reactivity with ADP-Ag between omeprazole and pantoprazole groups: 52±15% and 50±18% respectively, p=0.29. The present findings suggest the preferential use of pantoprazole compared to omeprazole in patients receiving clopidogrel to avoid any potential negative interaction with CYP2C19.