BackgroundMajor lower limb amputation (MLLA) is a life-saving procedure with significant morbidity and mortality. The objectives of this study were to determine the incidence of 30-day mortality, perioperative complications, and predictive risk factors of mortality in MLLA patients.MethodsThis retrospective cohort study included patients undergoing MLLA at The Aga Khan University Hospital, Pakistan, from January 2018 to December 2022. Data was collected using chart reviews and analyzed via Stata 15. Demographic, clinical, and procedural variables were examined. Predictive factors for 30-day mortality were assessed using Firth logistic regression.ResultsAmong 286 patients, the mean age was 49.4 +/- 20.9 years, and 79.4% were male. The leading indications for MLLA were diabetic foot (43.4%) and trauma (23.8%). Thirty-day mortality was 6.6%. Most deaths occurred in patients with diabetic foot (68.4%), chronic kidney disease (31.6%), or ischemic heart disease (36.8%). Below-knee amputation accounted for 68.4% of cases. Postoperative infections (11.2%) and stump necrosis (4.2%) were the most common complications. Multivariable analysis identified chronic kidney disease (OR: 3.613; 95% CI: 1.112-11.739; p = 0.033) and postoperative local wound infection (OR: 3.416; 95% CI: 1.036-11.267; p = 0.044) as significant predictors of 30-day mortality in this cohort.ConclusionMLLA is associated with considerable short-term mortality, particularly among patients with chronic kidney disease and postoperative surgical site infections. These findings emphasize the need for proactive identification of high-risk individuals, optimization of comorbid conditions, especially renal function, and strengthening perioperative infection control practices to improve patient outcomes in resource-limited settings.