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This analysis compares the procedural and acute angiographic outcomes in patients with critical limb ischemia (CLI) treated with orbital atherectomy in above-the-knee (ATK)/popliteal (POP) lesions versus below-the-knee (BTK) lesions.Lesion location affects the procedural outcomes and the opportunity for limb salvage in patients with CLI suffering from peripheral artery disease (PAD).The CONFIRM registry series was analyzed and includes 1109 real-world patients (1544 lesions) suffering from CLI treated with orbital atherectomy. The rates of dissection, perforation, slow flow, vessel closure, spasm, embolism, and thrombus formation were compared between CLI patients with ATK/POP lesions and BTK lesions.Patients with ATK/POP lesions had a higher final residual stenosis (10 vs. 9%;P= 0.004) and use of more adjunctive therapies (e.g. balloons and stents; 1.3 vs. 1.1%;P< 0.001) compared to patients with BTK lesions. Patients with BTK had higher incidence of perforation (1.5 vs. 0.2%;P= 0.005), slow flow (7.7 vs. 5.0%;P= 0.03) and spasm (10.3 vs. 4.2%;P <0.001) but lower incidence of embolism (0.4 vs. 5.1%;P< 0.001).Plaque modification with orbital atherectomy was successful in CLI patients regardless of lesion location. BTK lesions were associated with increased rates of perforation, slow flow and spasm which may be explained by more challenging procedural characteristics in these patients such as smaller vessel size and tortuosity. The higher incidence of emboli in ATK/POP lesions is most likely attributed to the higher prevalence of severe calcium observed in this cohort. © 2015 Wiley Periodicals, Inc.