Lack of quantitative, biomechanical criteria to predict the risk of fracture for a bone affected by giant cell tumor (GCT) has made the decision for the necessary surgical technique a dilemma. The purpose of this study is to critically assess the usefulness of quantitative computed tomography (QCT) based structural rigidity analysis (QCSRA) and QCT-based finite element analysis (FEA) in predicting the fracture risk for long bones reconstructed with bone cement. QCSRA, QCT-based FEA, and in-vitro mechanical tests on five pairs of cadaveric distal femora were employed to quantitatively assess the compressive failure load of the human femur affected by GCT and reconstructed with bone cement. QCT was utilized to investigate the bone’s structural rigidity properties as well as to generate heterogeneous finite element models using written material mapping codes. In order to validate the QCSRA and QCT-based FEA results, their outcomes were compared with the results of in-vitro mechanical tests on human cadavers. Results of this study demonstrated an acceptable correlation between QCSRA fracture loads and fracture loads found in in-vitro mechanical tests on cadavers (R² = 0.85). Also, QCSRA procedure is developed in order to estimate the axial stiffness and the maximum bending stiffness of the bone, employing the QCT-scans. It is shown that these two features, describing the structural rigidity, are linked to the experimental fracture loads (R² = 0.72 for axial stiffness, R² = 0.79 for maximum bending stiffness). Moreover, a good correlation was found between the fracture loads determined by QCT-based FEA and the experimental in-vitro fracture loads (R² = 0.92). Results of this study confirm the usefulness of the applications of QCSRA and QCT-based FEA as clinically tools for predicting the failure load of a long bone.