Study Design. Vertebral fracture load and stiffness from a metastatic vertebral defect model were predicted using nonlinear finite element models (FEM) and validated experimentally. Objective. The study objective was to develop and validate an FEM-based tool for predicting polymer-augmented lytic vertebral fracture load and stiffness and the influence of metastatic filling materials. Summary of Background Data. Percutaneous vertebroplasty has the potential to reduce vertebral fracture risk affected with lytic metastases by providing mechanical stabilization. However, it has been shown that the mismatch in mechanical properties between poly(methyl-methacrylate) (PMMA) and bone induces secondary fractures and intervertebral disc degeneration. A biodegradable copolymer, poly(propylene fumarate-co-caprolactone) (P(PF-co-CL)), has been shown to possess the appropriate mechanical properties for bone defect repair. Methods. Simulated metastatic lytic defects were created in 40 cadaveric vertebral bodies, which were randomized into 4 groups: intact vertebral body (intact), simulated defect without treatment (negative), defect treated with P(PF-co-CL) (copolymer), and defect treated with PMMA (PMMA). Spines were imaged with quantitative computed tomography (QCT), and QCT/FEM-subject-specific, nonlinear models were created. Predicted fracture loads and stiffness were identified and compared with experimentally measured values using Pearson correlation analysis and paired t test. Results. There was no significant difference between the measured and predicted fracture loads and stiffness for each group. Predicted fracture loads were larger for PMMA augmentation (3960 N [1371 N]) than that for the copolymer, negative and intact groups (3484 N [1497 N], 3237 N [1744 N], and 1747 N [702 N]). A similar trend was observed in the predicted stiffness. Moreover, predicted and experimental fracture loads were strongly correlated (R-2 = 0.78), whereas stiffness showed moderate correlation (R-2 = 0.39). Conclusion. QCT/FEM was successful for predicting fracture loads of metastatic, polymer-augmented vertebral bodies. Overall, we have demonstrated that QCT/FEM may be a useful tool for predicting in situ vertebral fracture load resulting from vertebroplasty.