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Amputations of the lower extremity remain a common procedure in a high-risk population. Perioperative morbidity and mortality reach as high as 14.1% in below-knee amputations. We aimed to determine whether regional, or neuraxial, anesthesia, when compared with general anesthesia (GA), would be associated with reduced perioperative morbidity and mortality.We queried the American College of Surgeons National Surgical Quality Improvement Program data set. The study population was divided into 2 groups: patients undergoing regional anesthesia (RA) and those undergoing GA. The primary end point for our study was 30-day mortality. The secondary end points were return to the operating room, surgical site infections, pulmonary complications, acute kidney injury, urinary tract infection, cardiac arrest, myocardial infarction, perioperative transfusions, thromboembolisms, sepsis, composite measure of postoperative complications, and days from operation to discharge.Twelve thousand seven hundred twenty-three patients were identified. Older patients, white patients, patients with a higher body mass index, patients without dyspnea, patients with independent functional status, smokers, patients with sepsis, and patients with bleeding disorders were associated with receiving GA. Hispanic patients, patients with chronic obstructive pulmonary disease, and patients with congestive heart failure were associated with receiving RA. Our study did not reveal a 30-day mortality difference between RA and GA. Regional anesthesia was associated with a significantly decreased need for perioperative blood transfusions (11.8% vs 16.5%, P < 0.001) and a decrease in the composite measure of postoperative complications (25.7% vs 29.1%, P < 0.04).Regional anesthesia does not offer a mortality advantage over GA, but RA may reduce the need for perioperative blood transfusions.