The impact of manipulating shear stress on conduit artery vasodilation has not been comprehensively described in vivo. We hypothesized that manipulation of SR through the brachial and radial arteries would be associated with corresponding changes in diameter. We performed a series of studies involving the following: (1) leg cycle exercise at increasing intensities (≈70 and 85% maximum heart rate [HRmax]) with simultaneous bilateral measurement of SR in the radial arteries; (2) leg cycle exercise for 30 minutes at 80% HRmax with simultaneous bilateral measurement of velocity and diameter in the brachial arteries; and (3) bilateral forearm heating for 30 minutes with simultaneous bilateral measurement of brachial artery diameter and blood velocity. Cycling and forearm heating interventions were performed in the presence of unilateral cuff inflation throughout the experiment, or starting during the intervention (15 minutes), to manipulate SR responses. Cuff placement was associated with lower radial artery SR responses (cuffed versus uncuffed, 248±49 versus 349±105 L/s 85% HRmax; P<0.01), and diameter responses were similarly attenuated (2.45±0.30 versus 2.78±0.20 mm 85% HRmax; P<0.05). Exercise performed at 80% HRmax in the presence of unilateral cuff inflation also reduced brachial artery SR (cuffed versus uncuffed; 258±107 versus 454±157 L/s; P<0.01) and diameter (3.96±0.39 versus 4.20±0.45 mm). Finally, cuff inflation decreased the impact of forearm heating on brachial SR (cuffed versus uncuffed; 262±97 versus 440±106 L/s; P<0.01) and diameter (4.35±0.54 versus 4.87±0.47 mm; P<0.05). Similar significant differences between the cuffed and uncuffed limbs in SR and diameter were observed when cuff inflation occurred during exercise or heating. Our findings strongly implicate SR as an important stimulus to increase conduit artery diameter in humans.