The lack of accuracy in the prediction of vertebral fracture risk from average density measurements, all external factors being equal, may not just be because bone mineral density (BMD) is less than a perfect surrogate for bone strength but also because strength alone may not be sufficient to fully characterize the structural failure of a vertebra. Apart from bone quantity, the regional variation of cancellous architecture would have a role in governing the mechanical properties of vertebrae. In this study, we estimated various microstructural parameters of the vertebral cancellous centrum based on stereological analysis. An earlier study indicated that within-vertebra variability, measured as the coefficient of variation (COV) of bone volume fraction (BV/TV) or as COV of finite element-estimated apparent modulus (E(FE)) correlated well with vertebral strength. Therefore, as an extension to our earlier study, we investigated (i) whether the relationships of vertebral strength found with COV of BV/TV and COV of E(FE) could be extended to the COV of other microstructural parameters and microcomputed tomography-estimated BMD and (ii) whether COV of microstructural parameters were associated with structural ductility measures. COV-based measures were more strongly associated with vertebral strength and ductility measures than average microstructural measures. Moreover, our results support a hypothesis that decreased microstructural variability, while associated with increased strength, may result in decreased structural toughness and ductility. The current findings suggest that variability-based measures could provide an improvement, as a supplement to clinical BMD, in screening for fracture risk through an improved prediction of bone strength and ductility. Further understanding of the biological mechanisms underlying microstructural variability may help develop new treatment strategies for improved structural ductility.