The role of trabecular microarchitecture in whole-vertebral biomechanical behavior remains unclear, and its influence may be obscured by such factors as overall bone mass, bone geometry, and the presence of the cortical shell. To address this issue, 22 human T9 vertebral bodies (11 female; 11 male; age range: 53–97 yr, 81.5 ± 9.6 yr) were scanned with μCT and analyzed for measures of trabecular microarchitecture, BMC, cross-sectional area, and cortical thickness. Sixteen of the vertebrae were biomechanically tested to measure compressive strength. To estimate vertebral compressive stiffness with and without the cortical shell for all 22 vertebrae, two high-resolution finite element models per specimen—one intact model and one with the shell removed—were created from the μCT scans and virtually compressed. Results indicated that BMC and the structural model index (SMI) were the individual parameters most highly associated with strength (R2 = 0.57 each). Adding microarchitecture variables to BMC in a stepwise multiple regression model improved this association (R2 = 0.85). However, the microarchitecture variables in that regression model (degree of anisotropy, bone volume fraction) differed from those when BMC was not included in the model (SMI, mean trabecular thickness), and the association was slightly weaker for the latter (R2 = 0.76). The finite element results indicated that the physical presence of the cortical shell did not alter the relationships between microarchitecture and vertebral stiffness. We conclude that trabecular microarchitecture is associated with whole-vertebral biomechanical behavior and that the role of microarchitecture is mediated by BMC but not by the cortical shell.