The recent reports of atypical femoral fracture (AFF) and its possible association with prolonged bisphosphonate (BP) use highlighted the importance of a thorough understanding of mechanical modifications in bone due to bisphosphonate treatment. The reduced compositional heterogeneity is one of the modifications in bone due to extensive suppression of bone turnover. Although experimental evaluations suggested that compositional changes lead to a reduction in the heterogeneity of elastic properties, there is limited information on the extent of influence of reduced heterogeneity on fracture resistance of cortical bone. As a result, the goal of the current study is to evaluate the influence of varying the number of unique elastic and fracture properties for osteons, interstitial bone, and cement lines on fracture resistance across seven different human cortical bone specimens using finite element modeling. Fracture resistance of seven human cortical bone samples under homogeneous and three different heterogeneous material levels was evaluated using a compact tension test setup. The simulation results predicted that the crack volume was the highest for the models with homogeneous material properties. Increasing heterogeneity resulted in a lower amount of crack volume indicating an increase in fracture resistance of cortical bone. This reduction was observed up to a certain level of heterogeneity after which further beneficial effects of heterogeneity diminished suggesting a possible optimum level of heterogeneity for the bone tissue. The homogeneous models demonstrated limited areas of damage with extensive crack formation. On the other hand, the heterogeneity in the material properties led to increased damage volume and a more variable distribution of damage compared to the homogeneous models. This resulted in uncracked regions which tended to have less damage accumulation preventing extensive crack propagation. The results also showed that the percent osteonal area was inversely correlated with crack volume and more evenly distributed osteons led to a lower amount of crack growth for all levels of material heterogeneity. In summary, this study developed a new computational modeling approach that directly evaluated the influence of heterogeneity in elastic and fracture material properties on fracture resistance of cortical bone. The results established new information that showed the adverse effects of reduced heterogeneity on fracture resistance in cortical bone and demonstrated the nonlinear relationship between heterogeneity and fracture resistance. This new computational modeling approach provides a tool that can be used to improve the understanding of the effects of material level changes due to prolonged BP use on the overall bone fracture behavior. It may also bring additional insight into the causes of unusual fractures, such as AFF and their possible association with long term BP use.