This study was conducted to investigate differences in brain response due to frontal and lateral impacts based on a partially validated three-dimensional finite element model with all essential anatomical features of a human head. Identical impact and boundary conditions were used for both the frontal and lateral impact simulations. Intracranial pressure and localized shear stress distributions predicted from these impacts were analyzed. The model predicted higher positive pressures accompanied by a relatively large localized skull deformation at the impact site from a lateral impact when compared to a frontal impact. Lateral impact also induced higher localized shear stress in the core regions of the brain. Preliminary results of the simulation suggest that skull deformation and internal partitions may be responsible for the directional sensitivity of the head in terms of intracranial pressure and shear stress response. In previous experimental studies using subhuman primates, it was found that a lateral impact was more injurious than a frontal impact. In this study, shear stress in the brain predicted by the model was much higher in a lateral impact in comparison with a frontal impact of the same severity. If shear deformation is considered as an injury indicator for diffuse brain injuries, a higher shear stress due to a lateral impact indicate that the head would tend to have a decreased tolerance to shear deformation in lateral impact. More research is needed to further quantify the effect of the skull deformation and dural partitions on brain injury due to impacts from a variety of directions and at different locations.