<p>The role of local hemodynamics on atherosclerosis at the carotid bifurcation has been the subject of study by computational fluid-dynamics (CFD) simulations for over three decades. Nevertheless, questions still swirl about the inherent rigid-wall assumption, especially with the introduction of increasingly predictive—but also increasingly intricate—hemodynamic parameters. Two-way-coupled fluid–structure interaction (FSI) simulations were performed on a cohort of 10 carotid bifurcations with ostensibly normal lumen geometries, along with CFD simulations assuming rigid arterial walls. In FSI simulations, carotid wall mechanical properties were assumed to be anisotropic via a fiber-reinforced hyperelastic material model, also accounting for prestress and external tissue support. Three-element Windkessel models were used to impose pressure conditions consistent with patient-specific measured inflow rates and outflow divisions. Maximum cross-sectional area changes over the cardiac cycle were generally less than 21%. Qualitatively, only small-to-moderate differences were observed between FSI and CFD simulations in terms of wall shear stress (WSS) and intravascular flow patterns. Quantitatively, median differences in the surface areas exposed to low time-averaged WSS (TAWSS), high oscillatory shear index (OSI) and topological shear variation index (TSVI) were 4.1%, 1.4%, and 2.3%, respectively, and co-localized satisfactorily (median similarity index: 0.83, 0.79, and 0.68, respectively). CFD simulations assuming arterial rigid walls are generally sufficient to adequately capture hemodynamic features of biological/clinical relevance, even for sensitive quantities like TSVI. However, the benefits of FSI for computation of structural quantities and the ability to explore the synergistic relationship between these quantities and hemodynamic stresses on the endothelium should not be overlooked.</p>