Abstract: Purpose: The purpose of this study was to understand health-related quality of life (HRQOL) factors for adults who experience major extremity trauma, including limb preservation and amputation, to guide the selection and creation of patient-reported outcome (PRO) measures. Methods: A thematic content qualitative analysis was used to study service members (SMs) with a history of major extremity trauma and clinical providers with expertise in limb trauma, limb loss, and limb preservation/reconstruction. Focus groups were conducted at three Military Treatment Facilities and one Department of Veterans Affairs Medical Center. Results: Fifty-six SMs and 34 clinicians participated. Thirty-six percent of focus group comments were coded under Physical Health, 31% Emotional Health, and 28% Social Participation. These results were largely consistent across clinicians and SMs, and clinical subgroups, with a few exceptions such as the relevance of fine motor tasks and prosthetic devices for SMs with upper extremity injury/limb loss, and orthotic devices for SMs with limb preservation/reconstruction. Conclusion: Many HRQOL topics identified are shared with existing general PRO measures—including pain, physical function, anxiety, depression, anger, positive affect and well-being, fatigue, social participation, and loneliness—as well as rehabilitation-focused PRO measures—such as resilience, grief/loss, stigma, self-esteem, mobility, fine motor functioning, self-care, and independence. This qualitative research can be used to inform domains of HRQOL in need of new PRO measures for this population, including satisfaction with orthosis/prosthesis, satisfaction with physical abilities/athleticism, body image, future outlook, and vocational impact.