The aim of this study was to evaluate the prognostic factors affecting mortality after major lower extremity amputations in patients with diabetes mellitus and peripheral vascular disease. For this retrospective study, 484 patients (345 male, 139 female) who were previously diagnosed with diabetes mellitus and peripheral vascular disease and underwent first-time nontraumatic major lower extremity amputations between January 2008 and January 2021 were included. The mean age of the patients was 64.2 ± 13.8 (20-114). In 32.4% of patients, peripheral vascular disease was the underlying cause, whereas diabetes mellitus was responsible for the etiology in 67.6% of patients. About 68.8% of patients had below-knee amputations, whereas 2.9% had bilateral below-knee amputations, 27.1% had above-knee amputations, and 1.2% had hip disarticulation performed. Gender, age, amputation level, amputation etiologies, Charlson comorbidity index, need for blood transfusion, and laboratory findings such as hemoglobin, platelet, albumin, erythrocyte sedimentation rate, C-reactive protein, sodium, potassium, and neutrophil to lymphocyte ratio levels were recorded preoperatively and at the time of discharge. Patients were grouped as died ≤1 month, ≤3 months, ≤6 months, and ≤12 months or alive. Advanced age, female gender, high Charlson comorbidity index, blood transfusion requirement, proximal amputation level, preoperative low platelet, preoperative low albumin, and parameters such as low hemoglobin, low erythrocyte sedimentation rate, high sodium, low platelet, low albumin, high C-reactive protein, and high neutrophil to lymphocyte ratio at time of discharge were seen to have a statistically significant effect on mortality at 1 month, 3 months, 6 months, and 12 months postoperatively. Preoperative high C-reactive protein had a statistically significant effect on mortality at 1 and 3 months postoperatively, whereas low C-reactive protein had a statisti cally significant effect on mortality at 6 months postoperatively. High potassium at the time of discharge was associated with mortality at 6 and 12 months postoperatively. This study has shown us that mortality rates are affected by modifiable parameters at the time of discharge such as hemoglo bin, sodium, potassium, platelet, and albumin, and normalization of these parameters before discharge could reduce the rates of mortality in the postoperative period. Level IV, Prognostic Study.