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The number of applications using neural prosthetic interfaces is expanding. Computer models are a valuable tool to evaluate stimulation techniques and electrode designs. Although our understanding of neural anatomy has improved, its impact on the effects of neural stimulation is not well understood. This study evaluated the effects of fascicle perineurial thickness, diameter, and position on axonal excitation thresholds and population recruitment using finite element models and NEURON simulations. The perineurial thickness of human fascicles was found to be 3.0% plusmn 1.0% of the fascicle diameter. Increased perineurial thickness and fascicle diameter increased activation thresholds. The presence of a large neighboring fascicle caused a significant change in activation of a smaller target fascicle by as much as 80% plusmn 11% of the total axon population. Smaller fascicles were recruited at lower amplitudes than neighboring larger fascicles. These effects were further illustrated in a realistic model of a human femoral nerve surrounded by a nerve cuff electrode. The data suggest that fascicular selectivity is strongly dependent upon the anatomy of the nerve being stimulated. Therefore, accurate representations of nerve anatomy are required to develop more accurate computer models to evaluate and optimize nerve electrode designs for neural prosthesis applications.