A number of human head finite element (FE) models have been developed from different research groups over the years to study the mechanisms of traumatic brain injury. These models can vary substantially in model features and parameters, making it important to evaluate whether simulation results from one model are readily comparable with another, and whether response-based injury thresholds established from a specific model can be generalized when a different model is employed. The purpose of this study is to parametrically compare regional brain mechanical responses from three validated head FE models to test the hypothesis that regional brain responses are dependent on the specific head model employed as well as the region of interest (ROI). The Dartmouth Scaled and Normalized Model (DSNM), the Simulated Injury Monitor (SIMon), and the Wayne State University Head Injury Model (WSUHIM) were selected for comparisons. For model input, 144 unique kinematic conditions were created to represent the range of head impacts sustained by male collegiate hockey players during play. These impacts encompass the 50th, 95th, and 99th percentile peak linear and rotational accelerations at 16 impact locations around the head. Five mechanical variables (strain, strain rate, strain × strain rate, stress, and pressure) in seven ROIs reported from the FE models were compared using Generalized Estimating Equation statistical models. Highly significant differences existed among FE models for nearly all output variables and ROIs. The WSUHIM produced substantially higher peak values for almost all output variables regardless of the ROI compared to the DSNM and SIMon models (p < 0.05). DSNM also produced significantly different stress and pressure compared with SIMon for all ROIs (p < 0.05), but such differences were not consistent across ROIs for other variables. Regardless of FE model, most output variables were highly correlated with linear and rotational peak accelerations. The significant disparities in regional brain responses across head models regardless of the output variables strongly suggest that model-predicted brain responses from one study should not be extended to other studies in which a different model is utilized. Consequently, response-based injury tolerance thresholds from a specific model should not be generalized to other studies either in which a different model is used. However, the similar relationships between regional responses and the linear/rotational peak accelerations suggest that each FE model can be used independently to assess regional brain responses to impact simulations in order to perform statistical correlations with medical images and/or well-selected experiments with documented injury findings.