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Trauma to the extremities is disproportionately represented in casualties of recent conflicts, accounting for >50% of injuries sustained during operations in Iraq and Afghanistan. Infectious complications have been reported in >25% of those evacuated for trauma, and 50% of such patients were treated in the intensive care unit (ICU). Osteomyelitis has been reported in 9% (14% of intensive care unit patients), and deep-wound infection in 27% of type III open-tibia fractures. Infections complicating extremity trauma are frequently caused by multidrug-resistant bacteria and have been demonstrated to lead to failure of limb salvage, unplanned operative take-backs, late amputations, and decreased likelihood of returning to duty. Invasive fungal infections of extremities have also presented a unique challenge in combat-injured patients, particularly in those with blast injuries with massive transfusion requirements and high injury severity scores. Infection prevention should begin at the time of injury and, although context-specific depending on the level of care, includes appropriate irrigation, surgical debridement, wound care and coverage, fracture fixation, and antibiotic prophylaxis, in addition to basic infection prevention measures. Clinical practice guidelines to address infection prevention after combat trauma (including extremity infection) were developed in 2007 and revised in 2011, with endorsement from the Surgical Infection Society and the Infectious Disease Society of America. Nevertheless, significant challenges remain, including austere environments of care, multiple transitions of care, and lack of coordinated efforts in prevention. Treatment of established infections is optimally multidisciplinary, particularly when deep wounds, bone, and joints are involved. Surgical debridement of overtly infected or necrotic tissue is necessary, with particularly aggressive margins if invasive fungal infection is suspected. Infected nonunion frequently requires the use of prosthetic materials for fixation, potentiating biofilm formation, and complicating medical therapy. Antibiotic therapy should be targeted at results of deep wound and bone cultures. However, this is complicated by frequent contamination of wounds, requiring differentiation between potential pathogens in terms of their virulence and decreased culture recovery in patient who have frequently received previous antibiotics. Lessons learned in infection prevention and treatment of orthopaedic trauma from combat can serve to inform the care of patients injured in natural disasters and noncombat trauma.