Flow recirculation zones and shear rate are associated with distinct pathogenic biological pathways relevant to thrombosis and atherogenesis. The interaction between stenosis severity and lesion eccentricity in determining the length of flow recirculation zones and peak shear rate in human coronary arteries in vivo is unclear. Computational fluid dynamic simulations were performed under resting and hyperemic conditions on computer-generated models and three-dimensional (3-D) reconstructions of coronary arteriograms of 25 patients. Boundary conditions for 3-D reconstructions simulations were obtained by direct measurements using a pressure-temperature sensor guidewire. In the computer-generated models, stenosis severity and lesion eccentricity were strongly associated with recirculation zone length and maximum shear rate. In the 3-D reconstructions, eccentricity increased recirculation zone length and shear rate when lesions of the same stenosis severity were compared. However, across the whole population of coronary lesions, eccentricity did not correlate with recirculation zone length or shear rate ( P = not signficant for both), whereas stenosis severity correlated strongly with both parameters ( r = 0.97, P < 0.001, and r = 0.96, P < 0.001, respectively). Nonlinear regression analyses demonstrated that the relationship between stenosis severity and peak shear was exponential, whereas the relationship between stenosis severity and recirculation zone length was sigmoidal, with an apparent threshold effect, demonstrating a steep increase in recirculation zone length between 40% and 60% diameter stenosis. Increasing stenosis severity and lesion eccentricity can both increase flow recirculation and shear rate in human coronary arteries. Flow recirculation is much more sensitive to mild changes in the severity of intermediate stenoses than is peak shear.