Introduction Major lower extremity amputation (LEA) results in significant morbidity and mortality. This study identifies factors contributing to adverse long-term outcomes after major LEA. Study Design Amputations in the Vascular Quality Initiative (VQI) long-term follow-up database from 2012 to 2017 were included. Multivariable logistic regression determined which significant patient factors were associated with 1-year mortality, long-term functional status, and progression to higher level amputation within 1 year. Results 3440 major LEAs were performed and a mortality rate of 19.9% was seen at 1 year. Logistic regression demonstrated that 1-year mortality was associated with post-op myocardial infarction (MI) (odds ratio (OR) 1.7, CI 1.02-2.97, P = .04), congestive heart failure (CHF) (OR 1.9, confidence interval (CI) 1.56-2.38, P < .001), hypertension (HTN) (OR 1.31, CI 1.00-1.72, P = .05), chronic obstructive pulmonary disease (COPD) (OR 1.36, CI 1.13-1.63, P < .001), and dependent functional status (OR 2.01, CI 1.67-2.41, P < .001). A decline in ambulatory status was associated with COPD (OR 1.36, CI 1.09-1.68, P = .006). Dependent functional status was protective against revision to higher level amputation (OR .18, CI .07-.45, P < .001). Conclusion In the VQI, 1-year mortality after major LEA is nearly 20% and associated with HTN, CHF, COPD, dependent functional status, and post-op MI. Decreased functional status at 1 year was associated with COPD, and progression to higher level amputation was less likely in patients with dependent functional status.