Major lower extremity amputation is a significant life-changing event that can have long-term implications. The goal of this study was to assess long-term medical outcomes and social determinants of health (SDH) challenges in this population. A retrospective review of major lower extremity (above ankle) amputations (2018-2022) was performed at a safety-net tertiary care center. Patients who participated in a SDH survey between 6-months to 1.5 years postoperatively were included for survey analysis. Patient demographics, comorbidities, and perioperative and long-term outcomes were analyzed. There were 100 patients included. Mean age was 61.5 years and 23% were of female gender. The majority (57%) were Black race, 20% White race, and 21% Hispanic ethnicity. Comorbidities included diabetes (78%), chronic kidney disease (51%), coronary artery disease (31%), congestive heart failure (23%), previous cerebrovascular events (19%), and 37% used opioids preadmission. At baseline, the majority (62%) lived at home. Guillotine amputation was performed in 24%, with definitive amputation below and above knee in 67% and 33%, respectively. Median length of stay was 7 days. Readmission at 30, 90 days, and 1-year was 13%, 30%, and 43% respectively. The average follow-up was 839 days. At long-term follow-up, 55% lived at home, 25% used opioids, and only 25% were independently ambulatory. In the SDH survey at follow-up, 32% identified at least one SDH challenge, with younger patients more often affected (58 vs. 63 years, P=.031). SDH challenges consisted of food insecurity (17%), housing insecurity (13%), transportation challenges (13%), seeking employment (8%), difficulty paying for utilities (5%) and medications (4%), seeking further education (5%), and difficulty caring for family/friends (4%). On multivariable analysis, having at least one SDH challenge was independently associated with 1-year readmission (OR 6.7, 95% CI 1.3-35.8, P<.001). Older age was associated with lower long-term independent ambulation (OR 0.92, 95% CI 0.85-0.99, P=.025). After major lower extremity amputation, patients have significant medical and social challenges with fewer living at home, the majority were not independently ambulatory, and one third having at least one SDH challenge. Improvements in long-term support including medical, social, and rehabilitation services are required for this vulnerable population.