Background and purpose: Mortality after major lower extremity amputations is high and may depend on amputation level. We aimed to examine the mortality risk in the first year after major lower extremity amputation divided into transtibial and transfemoral amputations.Methods: This observational cohort study used data from the Danish Nationwide Health registers. 11,205 first-time major lower extremity amputations were included from January 1, 2010, to December 31, 2021, comprising 3,921 transtibial amputations and 7,284 transfemoral amputations.Results: The 30-day mortality after transtibial amputation was overall 11%, 95% confidence interval (CI) 10–12 (440/3,921) during the study period, but declined from 10%, CI 7–13 (37/381) in 2010 to 7%, CI 4–11 (15/220) in 2021. The 1-year mortality was 29% overall, CI 28–30 (1,140 /3,921), with a decline from 31%, CI 21–36 (117/381) to 20%, CI 15–26 (45/220) during the study period. For initial transfemoral amputation, the 30-day mortality was overall 23%, CI 22–23 (1,673/7,284) and declined from 27%, CI 23–31 (138/509) to 22%, CI 19–25 (148/683) during the study period. The 1-year mortality was 48% overall, CI 46–49 (3,466/7,284) and declined from 55%, CI 50–59 (279/509) to 46%, CI 42–50 (315/638).Conclusion: The mortality after major lower extremity amputation declined in the 12-year study period; however, the 1-year mortality remained high after both transtibial and transfemoral amputations (20% and 46% in 2021). Hence, major lower extremity amputation patients constitute one of the most fragile orthopedic patient groups, emphasizing an increased need for attention in the pre-, peri-, and postoperative setting.