Knowledge of the location of initial regions of failure within the vertebra - cortical shell, cortical endplates vs. trabecular bone, as well as anatomic location--may lead to improved understanding of the mechanisms of aging, disease and treatment. The overall objective of this study was to identify the location of the bone tissue at highest risk of initial failure within the vertebral body when subjected to compressive loading. Toward this end, micro-CT-based 60-micron voxel-sized, linearly elastic, finite element models of a cohort of thirteen elderly (age range: 54-87 years, 75+/-9 years) female whole vertebrae without posterior elements were virtually loaded in compression through a simulated disc. All bone tissues within each vertebra having either the maximum or minimum principal strain beyond its 90th percentile were defined as the tissue at highest risk of initial failure within that particular vertebral body. Our results showed that such high-risk tissue first occurred in the trabecular bone and that the largest proportion of the high-risk tissue also occurred in the trabecular bone. The amount of high-risk tissue was significantly greater in and adjacent to the cortical endplates than in the mid-transverse region. The amount of high-risk tissue in the cortical endplates was comparable to or greater than that in the cortical shell regardless of the assumed Poisson's ratio of the simulated disc. Our results provide new insight into the micromechanics of failure of trabecular and cortical bone within the human vertebra, and taken together, suggest that, during strenuous compressive loading of the vertebra, the tissue near and including the endplates is at the highest risk of initial failure.