The functional significance of shear stress-induced vasodilatation in large conduit arteries is unclear since changes in the diameter have little effect on the resistance to blood flow. However, changes in diameter have a relatively large effect on wall shear stress which suggests that the function of flow-mediated dilatation is to reduce wall shear stress. The mean and pulsatile components of shear stress vary widely throughout the arterial system and areas of low mean and high amplitude of wall shear stress are prone to the development of atheroma. In this study, using an in vivo model with the ability to control flow rate and amplitude of flow independently, we investigated the characteristics of the response of the iliac artery to variations in both the mean and amplitude of wall shear stress. The results of this study confirm that increases in mean wall shear stress are an important stimulus for the release of nitric oxide by the endothelium as indicated by changes in arterial diameter and show for the first time, in vivo, that increases in the amplitude of the pulsatile component of shear stress have a small but significant inhibitory effect on this response. A negative feedback mechanism was identified whereby increases in shear stress brought about by increases in blood flow are reduced by the release of nitric oxide from the endothelium causing dilatation of the artery, thus decreasing the stimulus to cell adhesion and, through a direct action of nitric oxide, inhibiting the process of cell adhesion. The results also provide an explanation for the uneven distribution of atheroma throughout the arterial system, which is related to the ratio of pulsatile to mean shear stress and consequent variability in the production of NO. Flow-mediated dilatation of large conduit arteries was first demonstrated in vivo by Schretzenmayr (1933) and was later shown to be caused by the action of an increase in wall shear stress on the endothelium (Melkumyants et al. 1989) which causes vasodilatation by production of nitric oxide (NO) (Griffith et al. 1984). The functional significance of this dilatation is unclear since changes in the diameter of conduit arteries (e. g. aorta, iliac and femoral) have little effect on the resistance to blood flow, which is determined by the diameter of small-resistance arteries, in particular the arterioles. However, changes in diameter do have a relatively large effect on wall shear stress, which is inversely proportional to the diameter cubed at constant flow and viscosity, thus suggesting the existence of a negative feedback system whereby increases in wall shear stress, brought about, for example, by increases in flow, are reduced by dilatation of the conduit artery. Flow-mediated dilatation has also been directly observed in isolated small-resistance arteries (Sorop et al. 2003) and by implication from perfusion experiments in vivo (Kartamyshev et al. 2007). In these small arteries increases in diameter at constant pressure cause an increase in flow and the net effect of an increase i...