Abstract Background Patients with reduced responsiveness to clopidogrel often have diminished platelet inhibition, a factor associated with increased rates of major adverse cardiovascular events. Clinical trials that have focused on reducing high on-treatment platelet reactivity (HPR) with an additional loading dose of clopidogrel have reported varying effects. Prasugrel, a newer thienopyridine, exhibits a more consistent antiplatelet effect and more rapid onset time when compared to clopidogrel. We hypothesize that prasugrel reloading would be more effective than clopidogrel reloading in patients with HPR after an initial loading dose of clopidogrel. Method/Design Comparison of Prasugrel and Clopidogrel Reloading on High Platelet Reactivity in Clopidogrel-loaded Patients Undergoing Percutaneous Coronary Intervention (PRAISE-HPR) is a prospective, randomized, open-label, active controlled study. A total of 76 patients undergoing percutaneous coronary intervention (PCI), with HPR after administration of a loading dose of clopidogrel will be randomly assigned to either prasugrel or clopidogrel groups, and patients in each group will be reloaded with 20 mg of prasugrel or 300 mg of clopidogrel. The primary endpoint will be HPR at 24 hours after PCI, as determined by the VerifyNow assay during the study period. The rate of sustained high platelet reactivity and 30-day clinical outcomes will also be measured. Discussion PRAISE-HPR is a randomized controlled clinical trial to investigate the efficacy and safety of reloading prasugrel and clopidogrel in suppressing residual high platelet reactivity. The results will be made publicly available in the year 2013. Trial registration NCT01609647