The influence of wet and dry apparent density, apparent and real percentage of mineral, organic and water contents on the tension and shear fracture toughness, i.e., the mode I and mode II strain energy release rate (GIc and GIIc), respectively, was investigated for the human femur and the tibia. The results suggest that the water content, apparent density, and age were the best explanatory parameters for GIc and GIIc. Both GIc and GIIcsignificantly increase with increasing wet or dry apparent density. They also decrease with increasing water content; the decrease is nonsignificant for GIIc in the femur only. Mineral and organic percentage did not change in the bone with age, while the apparent percentages did change. Compositional parameters altogether can explain 35%–59% of the variation in fracture toughness. We conclude that bone composition and density have an important influence on fracture resistance of the cortical bone.