Hemodynamic shear stress is hypothesized to contribute to the localization of atherosclerotic plaques to certain arterial sites. Monocyte recruitment to these sites is an early event in atherogenesis. To determine the possible mechanisms by which shear stress modulates monocyte adhesion in vivo, studies of human monocytic cell adherence to endothelium were conducted under different shear conditions in a parallel-plate flow chamber. The number of monocytes capable of developing firm adhesive contacts with endothelium decreased as shear stress-induced drag forces increased over the range of 0.5 to 30 dynes/cm2. The number of adherent monocytic cells at a given shear stress was highly dependent on the activation state of the endothelium. To test the direct effect of shear stress on endothelial cell adhesivity, endothelial cells were presheared for 2 to 6 hr at 2, 10, or 30 dynes/cm2, and monocytic cell adherence was quantified at 1 dyne/cm2. Adherence increased 330% or 370% when endothelial cells were presheared for 2 hr at 2 or 10 dynes/cm2, respectively, as compared to unsheared endothelium. In contrast, when endothelial cells were presheared at 30 dynes/cm2, monocytic cell adherence at 1 dyne/cm2 was not significantly different from unsheared controls. Increased monocytic cell adherence to presheared endothelium was via a vascular cell adhesion molecule 1 (VCAM-1)/α4β1 mechanism, and enzyme-linked immunosorbent assay studies showed that pres-hearing at 2 dynes/cm2 for 2 hr increased endothelial VCAM-1 expression by 38%. These data demonstrate that low levels of shear stress induce endothelial VCAM-1 expression and increase monocytic cell adherence via a VCAM-1/α4β1 mechanism. Thus, shear stress can modulate monocyte adherence to vascular endothelium through drag forces that affect the establishment and maintenance of adhesive bonds and by directly modulating the expression of endothelial VCAM-1. This dual effect of shear stress produces the most favorable conditions for adhesion at low-shear regions, where drag forces are low and induction of VCAM-1 is likely. The preferential adherence of monocytes to these regions may contribute to the localization of atherosclerotic plaques to low-shear regions of the arterial circulation in vivo.