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Long-term results comparing percutaneous transluminal angioplasty with or without stenting (PTA/S) and open surgical bypass for chronic limb-threatening ischemia (CLTI) in patients who have had no prior intervention are lacking.All patients undergoing a first-time lower extremity revascularization for CLTI by vascular surgeons at our institution from 2005 to 2014 were retrospectively reviewed. Outcomes included perioperative complications, wound healing, restenosis, primary patency, reintervention, major amputation, RAS events (ie, reintervention, major amputation, or stenosis), and mortality. Outcomes were evaluated using χ2, Kaplan-Meier, and Cox regression analyses.Of the 2869 total lower extremity revascularizations performed between 2005 and 2014, there were 1336 that fit our criteria of a first-time lower extremity intervention for CLTI (668 bypass procedures and 668 PTA/S procedures). Bypass patients were younger (71 vs 72 years; P = .02) and more often male (62% vs 56%; P < .02). Total mean hospital length of stay (LOS) was significantly longer after a first-time bypass (10 vs 8 days; P < .001), as were mean preoperative LOS (4 vs 3 days; P < .01) and postoperative LOS (7 vs 5 days; P < .001). There was no difference in perioperative mortality (3% vs 3%; P = .63). Surgical site infection occurred in 10% of bypass patients. Freedom from reintervention was significantly higher in patients undergoing a first-time bypass procedure (62% vs 52% at 3 years; P = .04), as was freedom from restenosis (61% vs 45% at 3 years; P < .001). Complete wound healing at 6-month follow-up was significantly better after an initial bypass (43% vs 36%; P < .01). A Cox regression model of all patients showed that reintervention was predicted by a first-time PTA/S (hazard ratio, 1.6; 95% confidence interval, 1.3-2.1) and both preoperative femoropopliteal TransAtlantic Inter-Society Consensus (TASC) C and TASC D lesions (2.0 [1.3-3.1] and 1.8 [1.3-2.7], respectively). Major amputation among all patients was predicted by an initial presentation of gangrene (2.5 [1.3-5.0]), dialysis dependence (1.9 [1.3-2.9]), diabetes (2.0 [1.1-3.8]), and preoperative femoropopliteal TASC D lesions (2.1 [1.1-4.0]) and was not predicted by procedure type.In this retrospective analysis, bypass for the primary treatment of CLTI showed improved 6-month wound healing, higher freedom from restenosis, improved patency rates, significantly fewer reinterventions, and higher survival than PTA/S within 3 years; however, a bypass-first approach was associated with increased total hospital LOS and wound infection. Perioperative mortality and amputation rates were similar between procedure types.