Background Despite advancements in the diagnosis and treatment of peripheral vascular disease, major lower extremity amputations are still performed at high rates with non-negligible economic burdens. Perioperative morbidity and mortality is greater for patients who receive an above-knee amputation (AKA) compared to patients who receive a below-knee amputation (BKA). We sought to further evaluate what variables affect whether a patient receives a BKA versus an AKA using the Nationwide Inpatient Sample (NIS). Methods From 2005-2008, all adult AKA and BKA procedures were identified in the NIS. Patients with trauma and oncologic diagnoses were excluded from the analysis. Rates of AKA and BKA were evaluated according to patient demographics, comorbidities, extent of preamputation vascular intervention, hospital setting/type, and geographic region. Multivariate logistic regression and 2-way analysis of variance were used to determine statistical significance. Results A total of 228,624 patients met inclusion criteria (126,076 BKAs; 102,548 AKAs). Patients who received an AKA were more likely to be female (P < 0.0001), older (P < 0.0001), have nonprivate insurance (P < 0.0001), and have a higher Elixhauser Comorbidity Index score (P < 0.0001). Patients who received a BKA were more likely to have hypertension, diabetes, and a spinal cord injury (P < 0.0001). Fewer limb salvage vascular interventions were attempted in low-volume hospitals and in patients who subsequently received an AKA (P < 0.0001), while more limb salvage vascular interventions were performed at high-volume centers where more BKA procedures were performed (P < 0.0001). The majority of major amputations were performed in states in the southern United States (46.4%), and more BKA procedures were performed in urban and teaching hospitals (P < 0.0001). Conclusion Using the NIS database, we found important differences between patients who receive a BKA versus an AKA. These differences are broadly observed between patient demographics, race, comorbidities, insurance type, geographic region, and hospital type. Our findings highlight the need for more aggressive surveillance and preventative care of at-risk populations.