Metastatic lesions in the proximal femur can reduce hip strength and lead to pathologic fracture. However, current methods for identifying patients at risk of pathologic fracture are inadequate. We hypothesized the percentage of intact proximal femoral strength remaining after formation of a simulated lytic defect within the femoral neck or at the level of the lesser trochanter depends on defect location within the respective region. Computed tomography scan-based finite element models of 12 cadaveric proximal femora were used to evaluate the effect of 20-mm-diameter spherical voids at various locations in the neck and at the level of the lesser trochanter. In both regions, the percentage of intact strength remaining depended on defect location (p < 0.001). In the neck, the strength of specimens with inferomedial defects (median, 50.4% of intact; range, 27.8-71.7%) was less than the strength of specimens with defects located in the center of the neck, superolaterally, or anteriorly (p < 0.05). Near the lesser trochanter, anteromedial defects resulted in the lowest strength (median, 66.6% of intact; range, 49.2-73.8%). Other defects at the level of the lesser trochanter had a markedly smaller effect. These findings may be helpful for evaluating pathologic fracture risk.