Hypercapnia protects the blood-brain barrier against disruption during acute hypertension. Our goal was to determine whether protection of the blood-brain barrier by hypercapnia may be related to an affect of acidosis on the barrier, vasodilatation produced during hypercapnia, or attenuation of increases in cerebral venous pressure by hypercapnia. Pial vessels were examined in rats by means of fluorescent microscopy. We examined disruption of the blood-brain barrier in response to acute hypertension during hypercapnia (vasodilatation with acidosis), during topical adenosine (vasodilatation without acidosis), and during passive increases in cerebral venous pressure produced by venous occlusion during hypercapnia. Acute hypertension in normocapnic rats increased venular pressure and disrupted the blood-brain barrier and often produced bleeding from cerebral venules. Hypercapnia alone increased venular pressure, and acute hypertension produced only a modest further increase in venular pressure, with minimal disruption of the blood-brain barrier. Venous occlusion in hypercapnic rats increased venular pressure and disrupted the blood-brain barrier. We conclude that vasodilatation and acidosis produced by hypercapnia do not protect the blood-brain barrier from disruption during acute hypertension. Protection by hypercapnia during acute hypertension appears to be related to attenuation of increases in cerebral venous pressure.