The sacral region is the most common site for pressure ulcers (injuries) associated with lying in bed. Here we investigate the biomechanical efficacy of sacral prophylactic dressings in minimizing tissue stress concentrations when sustained bodyweight forces act. We specifically aimed to investigate the anisotropy features of materials and directional preference of stiffness properties in structures of multilayered dressings, and their contribution to efficacy. Furthermore, we simulate how fluids such as sweat or urine that may accumulate in the dressing over time may influence the protective efficacy of prophylactic dressings, in terms of extent of minimization of tissue stress exposures. In order to do so, multiple finite element model variants of the buttocks covered with prophylactic dressings of different designs were developed, and tissue stress distributions were determined when pure compressive bodyweight loading applies, and also for a combined compression and shear loading mode which reflects sliding in bed due to gravity. We have successfully developed an anatomically-realistic modeling framework for systematically comparing and rating strains and stresses in the soft tissues at the weight-bearing sacral region in supine weight-bearing on hospital mattresses, which now facilitate objective, quantitative and standardized evaluation of dressing technologies and associated performances.