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Pressure ulcers are localized damage to the skin and underlying tissues caused by sitting or lying in one position for a long time. Stresses within the soft tissue of the thigh and buttocks area play a crucial role in the initiating mechanism of these wounds. Therefore, it is crucial to develop reliable finite element models to evaluate the stresses caused by physiological loadings. In this study, we compared how the choice of material model and modeling area dimension affect prediction accuracy of a model of the thigh. We showed that the first-order Ogden and Fung orthotropic material models could approximate the mechanical behavior of soft tissue significantly better than neo-Hookean and Mooney–Rivlin. We also showed that, significant error results from using a semi-3D model versus a 3D model. We then developed full 3D models for 20 participants employing Ogden and Fung material models and compared the estimated material parameters between different sexes and locations along the thigh. We showed that males tissues are less deformable overall when compared to females and the material parameters are highly dependent on location, with tissues getting softer moving distally for both men and women. [ABSTRACT FROM AUTHOR]