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Retrograde popliteal artery (RPA) access to treat superficial femoral artery and popliteal artery disease is an option when treatment through common femoral artery (CFA) access is not possible. Our goal was to compare the safety and efficacy of RPA access with CFA access for treatment of femoral and popliteal artery lesions.The Vascular Quality Initiative was queried for all patients undergoing RPA access from 2010 to 2016 for symptomatic peripheral arterial disease. These were compared with standard CFA access. Patients with acute limb ischemia were excluded. Preoperative, operative, and postoperative data were analyzed. Perioperative and 6-month outcomes were analyzed. Multivariable analysis was used to assess the effect of RPA access on amputation or death, major adverse limb event (MALE) or death, patency, and death.There were 30,074 patients with isolated superficial femoral and popliteal artery disease treated, 148 of whom had RPA access. Indications overall included claudication (56.3%), rest pain (13.9%), and tissue loss (29.8%). RPA access had a significantly lower rate of technical success compared with CFA access (80.4% vs 93.8%; P < .001). RPA access and CFA access were similar for rates of arterial dissection (8.3% vs 6.3%; P = .333), distal embolization (0% vs 1.2%; P = .183), access site hematoma (3.4% vs 3.1%; P = .849), and 30-day mortality (1.4% vs 1.1%; P = .789). There were no differences between RPA access and CFA access for unadjusted 6-month amputation-free survival (94.8% vs 96%; P = .747) or survival (934.3% vs 95.6%; P = .845). MALE-free survival (74.5% vs 83.5%; P = .016) and patency (70.3% vs 83.1%; P < .001) were significantly lower in the RPA access group. Multivariable analysis showed no differences between patients who were successfully treated by RPA access and CFA access for amputation-free survival (hazard ratio [HR], 1.24; 95% confidence interval [CI], 0.46-3.32; P = .669), MALE-free survival (HR, 1.57; 95% CI, 0.99-2.5; P = .057), and survival (HR, 0.86; 95% CI, 0.43-1.73; P = .675). RPA access was independently associated with loss of primary patency (HR, 1.91; 95% CI, 1.24-2.94; P = .003).RPA access had lower technical success and primary patency compared with antegrade access at 6 months. There were no differences demonstrated between the two access techniques in perioperative morbidity and mortality or 6-month amputation, MALE, and survival. This technique should be considered when CFA access cannot be accomplished.