A noninvasive method for estimating regional myocardial contractility in vivo would be of great value in the design and evaluation of new surgical and medical strategies to treat and/or prevent infarction-induced heart failure. As a first step toward developing such a method, an explicit finite element (FE) model-based formal optimization of regional myocardial contractility in a sheep with left ventricular (LV) aneurysm was performed using tagged magnetic resonance (MR) images and cardiac catheterization pressures. From the tagged MR images, three-dimensional (3D) myocardial strains, LV volumes, and geometry for the animal-specific 3D FE model of the LV were calculated, while the LV pressures provided physiological loading conditions. Active material parameters ( and ) in the noninfarcted myocardium adjacent to the aneurysm (borderzone) and in the myocardium remote from the aneurysm were estimated by minimizing the errors between FE model-predicted and measured systolic strains and LV volumes using the successive response surface method for optimization. The significant depression in optimized relative to was confirmed by direct ex vivo force measurements from skinned fiber preparations. The optimized values of and were not overly sensitive to the passive material parameters specified. The computation time of less than 5 h associated with our proposed method for estimating regional myocardial contractility in vivo makes it a potentially very useful clinical tool.