BACKGROUND: Major limb amputation can place a significant financial burden on patients and their families because of costs of care and loss of income, encapsulated by the concept of financial toxicity. We sought to measure and understand factors associated with financial toxicity among patients undergoing major lower limb amputation for diabetic foot ulcers or peripheral arterial disease. METHODS: We identified patients in an institutional database who received lower limb amputations and excluded patients who underwent amputation due to known trauma or cancer. We administered the Financial Index of Toxicity survey, as well as a demographic survey. RESULTS: A total of 214 potentially eligible patients were identified, and 53 agreed to participate. The cohort included 34 males (64.2%) and had a mean age of 59.8 years. Amputation types included the following: 34 (64.2%) below-knee amputations, 16 (30.2%) above-knee amputations, and 3 (5.7%) hip disarticulations. The mean Financial Index of Toxicity total score for our sample was 37.8 (standard deviation 23.3). Factors associated with worse financial toxicity included higher age (P = 0.0002), fewer years of education (P = 0.007), employment before (P = 0.021) and unemployment after amputation (P = 0.005), and living in a zip code with lower population density (P = 0.024). CONCLUSIONS: Financial toxicity and unemployment after major lower limb amputation for diabetic foot ulcerations/peripheral arterial disease are high with more than 50% of our sample becoming unemployed after undergoing amputation. Financial toxicity is an important phenomenon after major lower limb amputation, and these data can be used to counsel vulnerable patients and support policy makers in appropriate resource allocation.