Severe DFIs are both limb threatening and life threatening and associated with nega-tive impact on health-related quality of life. Patients with DFI often have multiple comorbidities (cardiovascular, renal, neurologic, immunopathology) that increase the risk of morbidity and mortality. Significant risk factors for lower extremity amputa-tion include male gender, smoking, previous amputation, osteomyelitis, peripheral ar-tery disease, retinopathy, severe infections, gangrene, neuroischemic DFIs, leukocytosis, positive wound cultures, and isolation of gram-negative bacteria. The acute surgical management of severe infection takes priority over advanced diag-nostic workup. The presence of SIRS distinguishes severe infection from moderate infection. Bullae, tissue necrosis, ecchymosis, subcutaneous emphysema, petechiae, and/or crepitation are findings that herald the possibility of limb and life-threatening infections. Thorough drainage of abscesses and debridement of necrotic tissue are the goals of the initial surgery. Patients hospitalized with severe DFI require the exper-tise of a multidisciplinary, collaborative team for optimal medical and surgical outcomes. Once discharged from the inpatient setting, patients require vigilant follow-up. Postdischarge management may require advanced wound care, further surgical debridement, and future reconstructive surgery. Close inspection and surveil-lance of the contralateral "healthy" foot is necessary. The healthy foot experiences increased pressure and shear forces during the recovery process and is at risk for breakdown as well.