The goals of rehabilitation after major limb loss include not only functional restoration but also a return to a high quality of life (QOL). Few studies have identified which factors are associated with QOL in veterans and servicemembers with combat-associated major limb loss. We enrolled Vietnam and Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) veterans and servicemembers in a national survey on prosthetic device use. In the Vietnam group, multivariate analysis found multiple limb loss (adjusted odds ratio [aOR] = 3.1, 95% confidence interval [CI] = 1.57-6.02) and satisfaction with current prostheses (aOR = 1.2, 95% CI = 1.05-1.38) are associated with better overall QOL, while a higher amputation impact rank (aOR = 0.66, 95% CI = 0.59-0.74) and depression (aOR = 0.21, 95% CI = 0.08-0.54) are associated with worse overall QOL. In the OIF/OEF group, three factors are significantly associated with worse overall QOL: combat-associated head injury (aOR = 0.78, 95% CI = 0.61-0.99), combat-associated injury to the nonamputated limb (aOR = 0.71, 95% CI = 0.57-0.88), and assistance needed in daily living (aOR = 0.12, 95% CI = 0.02-0.72). Improving satisfaction with prosthetic devices, improving mental health care, and treating other combat-associated injuries may significantly improve the overall QOL for these veterans and servicemembers.