Purpose: Several methods have been proposed to simulate large breast compressions such as those occurring during x-ray mammography. However, the evaluation of these methods against real data is rare. The aim of this study is to learn more about the deformation behavior of breasts and to assess a simulation method. Methods: Magnetic resonance (MR) images of 11 breasts before and after applying a relatively large in vivo compression in the medial direction were acquired. Nonrigid registration was employed to study the deformation behavior. Optimal material properties for finite element modeling were determined and their prediction performance was assessed. The realism of simulated compressions was evaluated by comparing the breast shapes on simulated and real mammograms. Results: Following image registration, 19 breast compressions from 8 women were studied. An anisotropic deformation behavior, with a reduced elongation in the anterior-posterior direction and an increased stretch in the inferior-superior direction was observed. Using finite element simulations, the performance of isotropic and transverse isotropic material models to predict the displacement of internal landmarks was compared. Isotropic materials reduced the mean displacement error of the landmarks from 23.3 to 4.7 mm, on average, after optimizing material properties with respect to breast surface alignment and image similarity. Statistically significantly smaller errors were achieved with transverse isotropic materials (4.1 mm, P=0.0045). Homogeneous material models performed substantially worse (transverse isotropic: 5.5 mm; isotropic: 6.7 mm). Of the parameters varied, the amount of anisotropy had the greatest influence on the results. Optimal material properties varied less when grouped by patient rather than by compression magnitude (mean: 0.72 vs 1.44). Employing these optimal materials for simulating mammograms from ten MR breast images of a different cohort resulted in more realistic breast shapes than when using established material models. Conclusions: Breasts in the prone position exhibited an anisotropic compression behavior. Transverse isotropic materials with an increased stiffness in the anterior-posterior direction improved the prediction of these deformations and produced more realistic mammogram simulations from MR images.