Objectives Non-traumatic lower extremity amputation (LEA) is associated with significant morbidity and mortality. Diabetes mellitus (DM) and peripheral vascular disease (PVD) are associated with increased risk for LEA. As such, DM and PVD account for 54% of all LEA’s, performed in the United States annually. As obesity is highly associated with both DM and PVD, our study sought to explore the relationship between LEA and obesity defined by BMI. Methods Using the National Inpatient Sample (NIS) database, a retrospective review of patients who underwent non-traumatic LEA (LEA) between 2008 and 2014 was performed. The International Classification of Diseases 9th edition (ICD-9) codes were utilized to determine the diagnoses, comorbidities, and procedures. Patient BMIs were classified as follows: Non-obese [BMI Results We identified 16,259 patients with non-traumatic LEA and a mean age of 59.9 years. Rate of amputation in females was lower than males at 0.35% vs 0.87% respectively ( p < 0.001). Of patients that underwent amputation there was a V-shape trend based on BMI, with 30.4% in non-obese patients, 18.2% in obesity class I, 17.3% in obesity class II, and 34.1% in obesity class III. The incidence of diabetes increased with obesity class, while the incidence of PVD decreased. Interestingly, of those with DM there was an inverse relationship between amputation rate and BMI class, with LEA rates in non-obese versus obesity class III patients were 1.63% vs 0.98% respectively ( p < 0.001). Similarly, patients who had both diabetes and PVD showed a downward trend in LEA rate as obesity class increased; non-obese patients had a LEA rate of 8.01%, while obesity class III had 4.65% ( p < 0.001). Patients in higher income bracket have lower odds of LEA (OR 0.77, p < 0.001) compared to the lowest income patients. Also, patients with comorbidities such as PVD (OR 10.78), diabetes (OR 5.02), renal failure (OR 1.41), and hypertension (OR 1.36) had higher odds to get an LEA ( p < 0.001). Individuals with obesity class III are almost at half the odds (OR 0.52) to get an LEA compared to non-obese ( p < 0.001). Conclusions Higher BMI and female gender are protective factors against lower extremity amputation. Factors that predisposing to LEA include lower household income and certain comorbidities such as PVD, diabetes, renal failure, and hypertension. These findings warrant further research to identify patients at high risk for LEA and help develop management guidelines for targeted populations.