Increases in arterial carbon dioxide tension (hypercapnia) elicit potent vasodilation of cerebral arterioles. Recent studies have also reported vasodilation of the internal carotid artery during hypercapnia, but the mechanism(s) mediating this extracranial vasoreactivity are unknown. Hypercapnia increases carotid shear stress, a known stimulus to vasodilation in other conduit arteries. To explore the hypothesis that shear stress contributes to hypercapnic internal carotid dilation in humans, temporal changes in internal and common carotid shear rate and diameter, along with changes in middle cerebral artery velocity, were simultaneously assessed in 18 subjects at rest and during hypercapnia (6% carbon dioxide). Middle cerebral artery velocity increased significantly (69±10–103±17 cm/s; P<0.01) along with shear in both the internal (316±52–518±105 1/s; P<0.01) and common (188±40–275±61 1/s; P<0.01) carotids. Diameter also increased (P<0.01) in both carotid arteries (internal: +6.3±2.9%; common: +5.8±3.0%). Following hypercapnia onset, there was a significant delay between the onset of internal carotid shear (22±12 seconds) and diameter change (85±51 seconds). This time course is associated with shear-mediated dilation of larger conduit arteries in humans. There was a strong association between change in shear and diameter of the internal carotid (r=0.68; P<0.01). These data indicate, for the first time in humans, that shear stress is an important stimulus for hypercapnic vasodilation of the internal carotid artery. The combination of a hypercapnic stimulus and continuous noninvasive, high-resolution assessment of internal carotid shear and dilation may provide novel insights into the function and health of the clinically important extracranial arteries in humans.