Assess the burden and co-occurrence of pain, depression, and posttraumatic stress disorder (PTSD) among service members who sustained a major limb injury, and examine whether these conditions are associated with functional outcomes. A retrospective cohort study. Four U.S. military treatment facilities: Walter Reed Army Medical Center, National Naval Medical Center, Brooke Army Medical Center, and Naval Medical Center San Diego. Four hundred twenty-nine United States service members who sustained a major limb injury while serving in Afghanistan or Iraq met eligibility criteria upon review of their medical records. Not applicable. Outcomes assessed were: function using the short musculoskeletal functional assessment; PTSD using the PTSD Checklist and diagnostic and statistical manual criteria; pain using the chronic pain grade scale. Military extremity trauma and amputation/limb salvage patients without pain, depression, or PTSD, were, on average, about one minimally clinically important difference (MCID) from age- and gender-adjusted population norms. In contrast, patients with low levels of pain and no depression or PTSD were, on average, one to 2 MCIDs from population norms. Military extremity trauma and amputation/limb salvage patients with either greater levels of pain, and who experience PTSD, depression, or both, were 4 to 6 MCIDs from population norms. Regression analyses adjusting for injury type (upper or lower limb, salvage or amputation, and unilateral or bilateral), age, time to interview, military rank, presence of a major upper limb injury, social support, presence of mild traumatic brain injury/concussion, and combat experiences showed that higher levels of pain, depression, and PTSD were associated with lower one-year functional outcomes. Major limb trauma sustained in the military results in significant long-term pain and PTSD. Overall, the results are consistent with the hypothesis that pain, depression, and PTSD are associated with disability in this population. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.