Musculoskeletal modeling and simulations have become popular tools for analyzing human movements. However, end users are often not aware of underlying modeling and computational assumptions. This study investigates how these assumptions affect biomechanical gait analysis outcomes performed with Human Body Model and the OpenSim gait2392 model. The authors compared joint kinematics, kinetics, and muscle forces resulting from processing data from 7 healthy adults with both models. Although outcome variables had similar patterns, there were statistically significant differences in joint kinematics (maximal difference: 9.8° [1.5°] in sagittal plane hip rotation), kinetics (maximal difference: 0.36 [0.10] N·m/kg in sagittal plane hip moment), and muscle forces (maximal difference: 8.51 [1.80] N/kg for psoas). These differences might be explained by differences in hip and knee joint center locations up to 2.4 (0.5) and 1.9 (0.2) cm in the posteroanterior and inferosuperior directions, respectively, and by the offset in pelvic reference frames of about 10° around the mediolateral axis. The choice of model may not influence the conclusions in clinical settings, where the focus is on interpreting deviations from the reference data, but it will affect the conclusions of mechanical analyses in which the goal is to obtain accurate estimates of kinematics and loading.