Background: Historically, mortality rates after major lower limb amputations (LLAs) have been very high. However, there are inconsistencies regarding the risk factors. The reamputation rate after major LLAs is largely unknown. The aim of this study is to report the 30-day and 1-year mortality and 1-year reamputation rates after major LLA and to identify potential risk factors. Methods: An observational cohort study in which all patients undergoing dysvascular major LLA in 2012-2013 in 12 hospitals in the northern region of the Netherlands is included. Results: Of total 382 patients, who underwent major LLA, 65% were male and the mean age (standard deviation [SD]) was 71.9 +/- 12.5 years. Peripheral arterial disease was observed in 88% and diabetes mellitus (DM), in 56% of patients. No revascularization or prior LLA on the amputated side was observed among 26%, whereas 56% had no minor or major LLA on either limb before the study period. The 30-day and 1-year mortality rates were 14% and 34%, respectively. Patients aged 75-84 and >85 years had 3-4 times higher odds of dying within 1 year. Transfemoral amputations (odds ratio [OR], 2.2), history of heart failure (OR, 2.3), myocardial infarction (OR, 1.7), hemodialysis (OR, 5.7), immunosuppressive medication (OR, 2.8), and guillotine amputations (OR, 5.1) were independently associated with 1-year mortality. Twenty-six percent underwent ipsilateral reamputation within 1 year, for which no risk factors were identified. Conclusions: The mortality rate in the first year after major LLA is high, particularly among those undergoing transfemoral amputations, which is likely to be indicative of more severe vascular disease. Higher mortality among the most elderly patients, those with more severe cardiac disease and who underwent hemodialysis reflects the frailty of this population. Interestingly, DM, revascularization history, and prior minor or major LLA were not associated with mortality rates.