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Antiplatelet therapy has been a pillar of management for peripheral artery disease (PAD). However, a significant subset of patients with PAD will be resistant to certain antiplatelet medications and, therefore, have an increased risk of graft and/or stent thrombosis unknown to the surgeon. At present, no point-of-care testing to identity which patients will experience benefit from these medications has been incorporated into the treatment guidelines. Thromboelastography with platelet mapping affords an opportunity to evaluate real-time coagulation dynamics and platelet function. In the present prospective, observational study, we aimed to delineate the variation in response to antiplatelet therapy in patients with PAD undergoing revascularization.All patients who were undergoing named vessel revascularization during December 2020 through April 2022 were prospectively enrolled. Platelet mapping assays were performed in three clinical phases: preoperative, postoperative inpatient, and postoperative outpatient. The distribution of platelet reactivity within patients receiving mono- vs dual antiplatelet therapy was assessed, and a between-group inferential analysis was performed. The effect of comorbidities and intervention subtype on platelet inhibition was also analyzed.A total of 521 platelet mapping samples from 143 individual patients were analyzed using thromboelastography with platelet mapping. We found wide variability in the distribution of platelet inhibition, with a range of 0 to 100 and an interquartile range of 37.6. Although platelet inhibition with clopidogrel 75 mg was higher on average (44.8 ± 30.2) than that with aspirin 81 mg (24.6 ± 23.7) or aspirin 325 mg (27.1 ± 26.4; P = .001), clopidogrel at 75 mg demonstrated the highest variability in response.These data have demonstrated significant variability in the response to both mono- and dual antiplatelet therapy in PAD patients undergoing lower extremity revascularization. Future research on the effect of this variability in response on the clinical outcomes could provide invaluable understanding of the perioperative thrombotic risk.