Although the mode I (tensile opening) fracture toughness has been the focus of most fracture mechanics studies of human cortical bone, bones in vivo are invariably loaded multiaxially. Consequently, an understanding of mixed-mode fracture is necessary to determine whether a mode I fracture toughness test provides the appropriate information to accurately quantify fracture risk. In this study, we examine the mixed-mode fracture of human cortical bone by characterizing the crack-initiation fracture toughness in the transverse (breaking) orientation under combined mode I (tensile opening) plus mode II (shear) loading using samples loaded in symmetric and asymmetric four-point bending. Whereas in most structural materials, the fracture toughness is increased with increasing mode-mixity (i.e., where the shear loading component gets larger), in the transverse orientation of bone the situation is quite different. Indeed, the competition between the maximum applied mechanical mixed-mode driving force and the weakest microstructural paths in bone results in a behavior that is distinctly different to most homogeneous brittle materials. Specifically, in this orientation, the fracture toughness of bone is markedly decreased with increasing mode-mixity.