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Finite element (FE) models are very efficient tools to study internal stresses in human structures that induce severe pressure sores. Unfortunately, methods currently used to generate FE models are not suitable for clinical application involving wheelchair users. A clinical-oriented method, based on calibrated-biplanar radiographs, was therefore developed to generate a subject-specific FE model of the buttocks in a non-weighted sitting position. The model was then used to analyze the stress distribution within the buttocks and compare two wheelchair seat cushions designs. Additional radiographs and pressure measurements in a weighted sitting position were acquired to validate the FE model experimentally. Results from the FE model were in good agreement with experimental data and related literature. An internal peak pressure of 45.3 kPa was observed while seated on a flat foam cushion, corresponding to an interface pressure of 23.6 kPa. Both pressures occurred underneath the ischial tuberosities. When compared to the flat foam cushion, the contoured foam cushion reduced internal and interface peak pressures by 18% and 33%, respectively. The method developed in this study has a great potential for clinical use. The FE model, by predicting realistic stress distributions, allows for the selection of a convenient wheelchair seat cushion.