BACKGROUND Severe upper-extremity injuries account for almost one-half of all extremity trauma in recent conflicts in the Global War on Terror. Few long-term outcomes studies address severe combat-related upper-extremity injuries. This study's objective was to describe long-term functional outcomes of amputation compared with those of limb salvage in Global War on Terror veterans who sustained severe upper-extremity injuries. Limb salvage was hypothesized to result in better arm and hand function scores, overall functional status, and quality of life, with similar pain interference. METHODS This retrospective cohort study utilized data from the Military Extremity Trauma Amputation/Limb Salvage (METALS) study for a subset of 155 individuals who sustained major upper-extremity injuries treated with amputation or limb salvage. Participants were interviewed by telephone 40 months after injury, assessing social support, personal habits, and patient-reported outcome instruments for function, activity, depression, pain, and posttraumatic stress. Outcomes were evaluated for participants with severe upper-extremity injuries and were compared with participants with concomitant severe, lower-extremity injury. The analysis of outcomes comparing limb salvage with amputation was restricted to the 137 participants with a unilateral upper-extremity injury because of the small number of patients with bilateral upper-extremity injuries (n = 18). RESULTS Overall, participants with upper-extremity injuries reported moderate to high levels of physical and psychosocial disability. Short Musculoskeletal Function Assessment (SMFA) scores were high across domains; 19.4% screened positive for posttraumatic stress disorder (PTSD), and 12.3% were positive for depression. Nonetheless, 63.6% of participants were working, were on active duty, or were attending school, and 38.7% of participants were involved in vigorous recreational activities. No significant differences in outcomes were observed between patients who underwent limb salvage and those who underwent amputation. CONCLUSIONS Severe, combat-related upper-extremity injuries result in diminished self-reported function and psychosocial health. Our results suggest that long-term outcomes are equivalent for those treated with amputation or limb salvage. Addressing or preventing PTSD, depression, chronic pain, and associated health habits may result in less disability burden in this population. METHODS Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.