Hemodynamic forces play a role in determining endothelial cell (EC) phenotype and influence vascular remodeling. We present a lesion-based computational fluid dynamic (CFD) pilot analysis to understand the complex spatial and temporal hemodynamic changes that prevail in patients with high-grade carotid artery stenosis (CS). High-resolution three-dimensional (3D) rotational angiography datasets were acquired in eight patients, and used to generate computational meshes. CFD analysis was carried out implementing realistic shear-dependent viscosity for blood. The mean wall shear stress (WSS) within the stenosis region was 107 ± 73 dyn/cm2 rapidly followed by direction reversal and lower oscillating values in the recirculation zone at a mean of 19 ± 14 dyn/cm2. WSS vectors exhibited complex dynamic directional and amplitude oscillations not seen in healthy segments, along with time-dependent convergence and divergence strips during the cardiac cycle. The spatial gradient of WSS revealed an elevated average magnitude at the throat of the stenosis of 1425 ± 1012 dyn/cm3. In conclusion, patient-based CFD analysis of CS predicts a complex hemodynamic environment with large spatial WSS variations that occur very rapidly over short distances. Our results improve estimates of the flow changes and forces at the vessel wall in CS and the link between hemodynamic changes and stenosis pathophysiology.