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To analyze outcomes following major lower extremity amputations (mLEAs) for peripheral arterial obstructive disease, gangrene, infected non-healing wound and to create a risk prediction scoring system for 30-day mortality. In this single-center, retrospective, observational cohort study. All patients treated with above-the-knee amputation (AKA) or below-the-knee amputation (BKA) between January 1st, 2010 and June 30th, 2018 were identified. The primary outcome of interest was early (≤ 30 days) mortality. Secondary outcomes were postoperative complications and freedom from amputation stump revision/failure. We identified 310 (77.7%) mLEAs performed on 286 patients. There were 188 (65.7%) men and 98 (34.3%) women with a median age of 79 years (IQR, 69–83 years). We performed 257 (82.9%) AKA and 53 (17.1%) BKA. There were 49 (15.8%) early deaths, which did not differ among the age quartiles of this cohort (15.4% vs. 14.3% vs. 15.4% vs. 19.5%, P = 0.826). Binary logistic regression analysis identified age > 80 years (OR 2.24, 95% CI 1.17–4.31; P = 0.015), chronic obstructive pulmonary disease (OR 2.12, 95% CI 1.11–4.06; P = 0.023), and hemodialysis (OR 2.52, 95% CI 1.15–5.52; P = 0.021) to be associated with early mortality. The final score (range 0–10) identified two subgroups with different mortality at 30 days: lower-risk (score < 4, 10.8%), and higher-risk (score ≥ 4: 28.7%; OR 3.2, 95% CI 1.63–6.32; P < 0.001). In our experience, mLEAs still have a 14% mortality rate over the years. Our lower-risk group (score < 4) is characterized by a lower rate of perioperative death and longer survival. Graphic abstract