To associate the mechanical anisotropy of trabecular bone with the relationship between bone mineral density (BMD) and mechanical properties, 97 cubic specimens of human trabecular bone were imaged with computed tomography. Bone cubes from the spine, the calcaneus, the distal, and the proximal femur were tested multidirectionally to measure their compressive stiffness and to calculate their ratios of mechanical anisotropy. The ultimate strength was determined in a destructive test in cephalo-caudal (c-c) direction. Compressive stiffness was largest in the c-c direction for the specimens from the spine, as well as the distal and the proximal femur, but not the calcaneus. Anisotropy ratios in c-c direction were larger at the distal femur and the spine than in the proximal femur. The predictive power of BMD for the mechanical properties varied with anatomical location and strongly depended on the loading direction. While at the spine the c-c stiffness was highly correlated to BMD (r2 = 0.73), the perpendicular directions showed only modest correlations (r2 < 0.53). The correlations of mechanical properties with BMD were greatest at locations where the anisotropy was less pronounced (proximal femur) or rather uniform (spine). The data suggest that BMD can be most successfully applied to determine the mechanical properties in the principal loading direction, which from a clinical perspective may be most relevant.