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Assess effectiveness of Injury Severity Score (ISS) in predicting injury severity in combat-related amputations.Retrospective evaluation of prospectively collected data.Military medical center.One hundred and nine patients with major extremity amputations sustained in overseas combat.Standard combat casualty care.Difference in injury severity as measured by ISS, numbers of extremity(s) amputated, number of associated injuries, blood products used, intensive care unit length of stay, hospital length of stay in those with an upper extremity amputation (UEA) compared with those with an isolated lower extremity amputation.Thirteen patients (11.9%) sustained at least one UEA. Patients with an UEA had a greater number of amputations per casualty compared with patients with a lower extremity alone (2.5 vs. 1.5; P < 0.001). The mean hospital length of stay (P = 0.02) and intensive care unit length of stay (P = 0.02) were significantly greater in those with an UEA. Mean blood product utilization was also significantly greater in those with an upper extremity amputation (P < 0.05). There was no difference in ISS between the two groups (P > 0.05).The presence of an UEA is associated with increased injury severity as evident by increased intensive care unit requirements, blood product utilization, and hospital length of stay. ISS underestimates the severity of injury and therefore resource utilization in patients with multiple combat-related amputations. Recognition of this limitation in addition to the development of a military-specific ISS is required for more effective resource utilization to continue to improve combat casualty care.Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.