Background: Adding cilostazol (100mg bid) to dual antiplatelet therapy (Triple antiplatelet therapy, TAPT) can inhibit enhanced platelet activation in high-risk patients. Although proton pump inhibitor (PPI) is added to oral antiplatelet therapy in cardiovascular disease patients to reduce the risk of GI bleeding, attenuated antiplatelet effect by PPI administration has been a matter of concerns. The aim of this study was to assess the antiplatelet effect of TAPT in high-risk patients receiving PPI. Method: After acute myocardial infarction (AMI) patients were treated with coronary stenting (n=88), patients were randomly assigned to receive either TAPT with 20mg/d omeprazole (triple group; n=44) or 150mg/d double-dose clopidogrel with 20mg/d omeprazole (double-dose group; n=44). Platelet reactivity (PR) was evaluated at predischarge and 30-day follow-up by light trasmittance aggregometry (LTA) and VASP assay. Primary end point was 20M ADP-induced maximal platelet aggregation (MPA) at 30-day. High on-treatment PR (HPR) was defined as 20M ADP-induced MPA >59%, based on the consensus paper. Results: Predischarge platelet measures were similar in both groups. At 30-day follow-up, MPAs with 20 and 5關M ADP stimuli were significantly decreased in the triple group compared with the double-dose group (33.3짹16.6% vs. 47.2짹17.7%, P <0.001 and 23.4짹14.0% vs. 35.1짹15.7%, P <0.001, respectively). Results were consistent in ADP-induced late PAs. After the addition of 0.5mM arachidonic acid and 6g/mL collagen, the triple group also tended to achieve the lower levels of 30-day MPA (12.0짹14.2% vs. 16.6짹9.1%, P =0.124 and 31.7짹18.8% vs. 41.0짹18.9%, P =0.050, respectively) than the double-dose group. In addition, 30-day platelet reactivity index by VASP assay was lower in the triple vs. double-dose group (40.0짹14.8% vs. 47.9짹15.8%, P =0.019). The prevalence of 30-day HPR was significantly lower in the triple group compared with the double-dose group (6.8% vs. 27.3%, P =0.011). In multivariate analysis, the administration of adding cilostazol was a negative predictor for the risk of HPR (Odds ratio 0.20, 95% confidence interval 0.04 to 0.93, P =0.040). Conclusions: Despite the coadministration of omeprazole, adding cilostazol to dual antiplatelet therapy in stented AMI patients achieves enhanced platelet inhibition and reduces the risk of HPR as compared with double-dose clopidogrel.