Background: The objective of the study was to compare bypass surgery and endovascular revascularization of the femoropopliteal segment in patients with peripheral arterial disease and critical limb-threatening ischemia (CLTI). Methods: This is a single-center study including patients undergoing first-time lower extremity intervention with peripheral bypass surgery or percutaneous transluminal angioplasty with or without stenting (PTA/S) of the femoropopliteal segment because of CLTI from 2011 to 2015. Based on prospective entered data from the Danish Vascular Registry, the primary end points were amputation-free survival, overall mortality, and reinterventions. Results: A total of 679 patients with CLTI were included of which 35% (n = 239) were treated with PTA/S, 54% (n = 363) with vein bypass, and 11% (n = 77) with synthetic bypass. After 3 years, amputation-free survival was significantly better with a vein bypass (41.8% [95% CI: 35–48.4]) than both PTA/S (29.7% (95% CI: 22.7–37)) and synthetic bypass (31.7% [95% CI: 19–45.1]). Overall, the endovascular-treated patients faced more than 50% increased risk of major amputation or death than that of a vein bypass, after adjusting for comorbidity and Trans-Atlantic Inter-Society Consensus (TASC) classification (HR: 1.56 [95% CI: 1.21–2.05]). As expected, postoperative complications, length of hospital stay, and reinterventions were more frequent in the bypass groups. Conclusions: In this nonrandomized study, autologous vein bypass was superior to both PTA/S and synthetic bypass in regard to amputation-free survival and overall mortality. Despite the increased frequency of surgical complications, a vein bypass appears justified in both shorter (TASC B-C) and longer (TASC D) femoropopliteal lesions.