OBJECTIVES Determine the incidence, severity, and associated risk factors for the development of low bone mineral density (BMD) after combat-related lower extremity amputation. DESIGN Retrospective case-control comparison. SETTING Tertiary care military treatment facility. PATIENTS/PARTICIPANTS One hundred fifty-six lower extremity amputees, representing 182 amputations (121 unilateral, 35 bilateral). INTERVENTION All patients underwent dual energy x-ray absorptiometry scanning during the treatment period. MAIN OUTCOME MEASUREMENTS The Z score was the main outcome measure. We identified all patients with low BMD (Z < -1.0) and conducted multivariate analysis to identify significant risk factors for low BMD development. RESULTS The observed rate of low BMD was 42%. The average Z score was -0.6 ± 1.1 among unilateral amputations and -1.2 ± 1.0 among bilateral amputations (P = 0.005). Risk factors for the development of low BMD were prolonged time to first ambulation [odds ratio (OR) = 1.39; 95% confidence interval (CI): 1.003-1.93; P = 0.048], prolonged time to dual energy x-ray absorptiometry (OR = 1.10; 95% CI: 1.02-1.18; P = 0.009), and more proximal amputation level (OR = 7.27; 95% CI: 3.21-16.49; P < 0.001). Among unilateral amputees, we detected a significant difference in the BMD of the intact and amputated limbs (-1.0; 95% CI: -1.1 to -0.8; P < 0.001). CONCLUSIONS Proximal amputation level and delayed ambulation demonstrated a significant relationship with low BMD after traumatic and trauma-related amputation. We conclude that transfemoral amputees are at greater risk of BMD loss and that disuse atrophy is a primary factor in the development of low BMD. Prevention should focus on early and aggressive weight bearing rehabilitation and assessing levels and appropriately supplementing calcium and vitamin D.