Background The above-knee amputation (AKA) is an operation of last resort with high postoperative morbidity and mortality. This study identifies preoperative risk factors predictive of both 30-day mortality and extended length of stay (LOS) in AKA patients. Methods Two hundred ninety-five AKA patients from 2004 to 2013 from a single institution were retrospectively reviewed using a deidentified electronic medical record. Rationally selected factors potentially influencing 30-day mortality and LOS were chosen, including demographics, etiologies, vascular surgical history, lifestyle factors, comorbidities, and laboratory values. Variables trending with one of the end points on bivariate analysis (P ≤ 0.10) were entered into multivariate forward stepwise regression models to determine independence as a risk factor (P ≤ 0.05). Subgroup analysis of AKA patients without a traumatic, burn, or malignant etiology was similarly conducted. Results Within the 295 patient cohort, 60% of the patients were male, 18% were African American, mean age was 58 years and mean body mass index was 28 kg/m2. The 30-day mortality rate was 9%, and mean postoperative LOS of discharged patients was 9.3 days. Upon logistic regression, thrombocytopenia (platelet count < 250 × 106/mL, P < 0.001, odds ratio 6.1) and preoperative septic shock (P = 0.02, odds ratio 5.1) were identified as independent risk factors for 30-day mortality. Upon linear regression, burn etiology (P < 0.001, B = 15.8 days), leukocytosis (white blood cell count > 12 × 106/mL, P < 0.001, B = 6.2 days), and guillotine amputation (P < 0.001, B = 7.6 days) were independently associated with prolonged LOS. Excluding patients with AKAs due to trauma, burn, or malignancy, only thrombocytopenia (platelet count < 250 × 106/mL, P < 0.001, odds ratio 10.2) and leukocytosis (white blood cell count > 12 × 106/mL, P = 0.01, B = 5.2 days) were independent risk factors for in-hospital mortality and prolonged LOS, respectively. Conclusions Preoperative septic shock and thrombocytopenia are independent risk factors for 30-day mortality after AKA, while burn etiology, leukocytosis, and guillotine amputation contribute to prolonged LOS. Awareness of these risk factors may help enhance both preoperative decision making and expectations of the hospital admission.