Abstract Background The Best Endovascular versus Best Surgical Therapy in Patients with Chronic Limb Threatening Ischemia (CLTI) (BEST-CLI) trial randomized 1830 subjects with chronic limb threatening ischemia (CLTI) to endovascular or surgical bypass revascularization. Major adverse limb events (MALE) were higher after endovascular revascularization compared to bypass in the cohort with bypass using adequate single segment great saphenous vein. However, 15% of endovascular procedures had a major endpoint due to lack of technical success of the index procedure. Purpose To assess the factors related to a MALE in subjects in the BEST-CLI trial with an initial endovascular procedure that was technically successful. Methods All patients with a technically successful endovascular procedure (defined as a residual stenosis < 50% in the superficial femoral, popliteal, and/ or tibial arteries with in-line flow to the foot) were included. MALE was defined as above ankle amputation of the index limb or a major index-limb reintervention (new bypass, interposition graft revision, thrombectomy, or thrombolysis). Patient, procedure, and limb characteristics at the time of the index procedure were compared to the risk of MALE over an average 2.7 years follow-up. Characteristics were compared with the Kruskal-Wallis or Chi-square tests as appropriate. Results Of 923 patients having endovascular therapy as the index revascularization, 773 (84%) had a technically successful procedure. The cause of failure in 122 (82%) of unsuccessful procedures was the inability to cross the lesion with a wire. Significant patient factors associated with MALE included younger age (64 vs 68 years, p<0.0001), current smoking (44% vs 33%, p=0.004), and end-stage renal disease (17% vs 10%, p=0.013). Diabetes mellitus was not associated with MALE (74% vs 68%, p=0.08). Significant limb characteristics associated with MALE included lesions treated in the superficial femoral (SFA) or above knee popliteal artery (87% vs 81%, p=0.042), length of lesion in the SFA or above knee popliteal artery (201 cm vs 172 cm, p=0.02), use of atherectomy and bare-metal stent (10% vs 5%, p=0.01), and total procedure time (172 vs 155 min, p=0.002). Lesions treated in the below-knee popliteal artery or tibial arteries (62% vs 62%, p=0.93) or lesion length in this region (134 vs 144 cm, p=0.70) were not related to the risk of MALE. Conclusions The risk of MALE after successful endovascular revascularization for CLTI was increased with younger age, current smoking, end-stage renal disease, longer lesion length, treatment of the SFA to above knee popliteal arteries, and treatment with atherectomy with bare-metal stenting. Treatment of below knee lesions were not associated with MALE. These results indicate the importance of both modifiable and non-modifiable patient factors as well as the anatomic location of disease in determining limb outcomes in CLTI.