Biomechanical investigations of orthopedic fracture fixation constructs increasingly use analogs like the third and fourth generation composite femurs. However, no study has directly compared cortical screw purchase between these surrogates and human femurs, which was the present aim. Synthetic and human femurs had bicortical orthopedic screws ( and ) inserted in three locations along the anterior length. The screws were extracted to obtain pullout force, shear stress, and energy-to-pullout. The four study groups ( femurs each) assessed were the fourth generation composite femur with both 16 mm and 20 mm diameter canals, the third generation composite femur with a 16 mm canal, and the human femur. For a given femur type, there was no statistical difference between the proximal, center, or distal screw sites for virtually all comparisons. The fourth generation composite femur with a 20 mm canal was closest to the human femur for the outcome measures considered. Synthetic femurs showed a range of average measures (2948.54–5286.30 N, 27.30–35.60 MPa, and 3.63–9.95 J) above that for human femurs (1645.92–3084.95 N, 17.86–24.64 MPa, and 1.82–3.27 J). Shear stress and energy-to-pullout were useful supplemental evaluators of screw purchase, since they account for material properties and screw motion. Although synthetic femurs approximated human femurs with respect to screw extraction behavior, ongoing research is required to definitively determine which type of synthetic femur most closely resembles normal, osteopenic, or osteoporotic human bone at the screw-bone interface.