Major lower extremity amputations continue to be associated with significant morbidity and mortality, yet few recent large series have evaluated factors associated with perioperative mortality and wound complications. The purpose of this study was to examine factors affecting perioperative mortality and wound-related complications following major lower extremity amputation. A retrospective review was conducted of all adult patients who underwent nontraumatic major lower extremity amputations over a 5-year period at a single tertiary-care center in southern West Virginia. Demographic and clinical data, perioperative data, and outcomes were collected and analyzed to identify any relationship with perioperative mortality, as well as wound complications and early revisions (within 90 days) to a more proximal level. Variables were examined using chi-squared, two-tailed t-tests, and logistic regression. Three hundred eighty patients (61% male) underwent 412 major lower extremity amputations during 1999-2003. The initial level of amputation included 230 below-knee (BKA), 149 above-knee (AKA), and one hip disarticulation. Perioperative mortality was 15.5% (n = 59). From a regression model, age, albumin level, AKA, and lack of a previous coronary artery bypass graft (CABG) were independently related to mortality. Patients who did not have a previous CABG were nearly three times more likely to die than those who did (p = 0.038). Overall early wound complications were noted in 13.4% (n = 51). Four factors were independently related to experiencing a 90-day wound complication: BKA, community (rather than care facility) living, type of anesthesia, and preoperative hematocrit >30%. Major lower extremity amputation in patients with peripheral vascular disease continues to be associated with considerable perioperative morbidity and mortality. Even though the surgical procedure itself may not be challenging from a technical standpoint, underlying medical conditions put this group at high risk for perioperative death. Wound-healing problems are frequently encountered and must be minimized to facilitate early mobilization and hospital discharge.