Background Treatment with clopidogrel is subject to wide variability in response, and high on-treatment platelet reactivity (HTPR) is associated with increased risk of ischemic events. Ticagrelor has been shown to have antiplatelet effects superior to those of clopidogrel, with subsequent reduced clinical ischemic events. However, the efficacy of ticagrelor in high-risk patients with coronary disease who have high on-treatment platelet reactivity (HTPR) with clopidogrel has not been examined. Methods We recruited 201 patients (mean age, 64 ± 10 years; 20% women) with stable/unstable angina who were receiving clopidogrel treatment and in whom coronary catheterization was planned. Platelet reactivity was tested using VerifyNow P2Y12 assay (Accumetrics, San Diego, CA) (HTPR defined as P2Y12 reaction units [PRU] ≥ 208). Patients with HTPR were randomized to receive either additional clopidogrel 300 mg or ticagrelor 180 mg before coronary angiography, and persisted with the respective treatment after percutaneous coronary intervention (PCI). The primary end point was the rate of troponin elevation after PCI, and the secondary end point was the change in platelet reactivity 24 hours after PCI. In addition, clinical outcomes at 30 days were evaluated. Results Eighty-four (42%) patients had HTPR (mean PRU, 270.8 ± 46.5) and were randomly assigned to clopidogrel or ticagrelor treatment. Subsequently, 49 patients underwent percutaneous coronary intervention (PCI) (26 receiving ticagrelor and 23 receiving clopidogrel). After PCI, the mean PRU in the ticagrelor group declined significantly (ticagrelor, 59.3 ± 49 vs clopidogrel, 202.4 ± 60.4; P < 0.0001). The rate of cardiac troponin elevation and clinical ischemic events were similar between the groups. Conclusions In high-risk patients with coronary disease and HTPR on clopidogrel, ticagrelor was highly effective in platelet inhibition and overcoming HTPR compared with continued clopidogrel treatment but had no apparent effect on troponin release or short-term clinical outcomes.