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Pathologic fractures of femora in patients with metastatic cancer are associated with high morbidity and mortality. Prediction of impending fractures is based on unspecific clinical criteria or past clinician's experience, which leads to underestimation or overtreatment. The aim of this study was to investigate the effect of the site of metastatic lesions on biomechanical behavior of the proximal femur. Sixteen pairs of human femora were scanned with quantitative computed tomography (QCT) to asses bone mineral density. One femur of each pair remained intact while a defined lesion was reamed out in either the superolateral or inferomedial portion of the femoral neck of the contralateral femur. All femora were loaded in a mechanical test setup mimicking one-legged stance and stiffness, failure load, and fracture location were determined. In the biomechanical experiments the superolateral lesion and the inferomedial lesion caused a stiffness reduction of 19% and 66%, respectively. The average failure load was 40% and 75% lower for specimens with the superolateral (4.53 ± 1.56 kN) and inferomedial (1.89 ± 1.73 kN) lesions, respectively, compared to intact specimens (7.66 ± 3.34 kN). Lesions in the femoral neck led to reduction in both stiffness and failure load of the proximal femur. Furthermore, the site of the lesion had a large effect on the magnitude of the reduction in biomechanical properties. The presented data emphasize the importance of differentiating between locations of the lesion in pathologic fracture prediction of the metastatic femur and underline the insufficient accuracy of current predictive guidelines. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2407-2414, 2017., (© 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)