Predicting pathologic fractures in femora with metastatic lesions remains a clinical challenge. Currently used guidelines are inaccurate, especially to predict non-impeding fractures. This study evaluated the ability of a nonlinear quantitative computed tomography (QCT)-based homogenized voxel finite element (hvFE) model to predict patient-specific pathologic fractures. The hvFE model was generated highly automated from QCT images of human femora. The femora were previously loaded in a one-legged stance setup in order to assess stiffness, failure load, and fracture location. One femur of each pair was tested in its intact state, while the contralateral femur included a simulated lesion on either the superolateral- or the inferomedial femoral neck. The hvFE model predictions of the stiffness (0.47 < R2 < 0.94), failure load (0.77 < R2 < 0.98), and exact fracture location (68%) were in good agreement with the experimental data. However, the model underestimated the failure load by a factor of two. The hvFE models predicted significant differences in stiffness and failure load for femora with superolateral- and inferomedial lesions. In contrast, standard clinical guidelines predicted identical fracture risk for both lesion sites. This study showed that the subject-specific QCT-based hvFE model could predict the effect of metastatic lesions on the biomechanical behaviour of the proximal femur with moderate computational time and high level of automation and could support treatment strategy in patients with metastatic bone disease.