An isolated cerebral arteriole preparation was used to test the hypothesis that a temporary reduction in transmural pressure causes a subsequent vasodilation mediated by mechanisms intrinsic to the vessel wall. Thrity-five cerebral vessels of 44.7 ± 1.4μM (± standard error of the mean) mean diameter were cannulated in vitro and pressurized at a transmural pressure of 60 mm Hg; after an equilibration period the vessels developed spontaneous tone. When transmural pressure was decreased to 0 mm Hg for a period of 4 minutes then returned to 60 mm Hg, vessels dilated to 155.1% ± 6.8% of control diameter before gradually redeveloping spontaneous tone in 5.5 ± 0.7 minutes. Varying the duration of the period during which transmural pressure was at 0 mm Hg had significant effect on the degree of vasodilation. Conversely, varying the level of decreased transmural pressure between 0 and 20 mm Hg significantly affected both the magnitude of vasodilation and the time course of spontaneous tone recovery. These findings indicate that a temporary period of decreased transmural pressure may result in a loss of spontaneous tone in the resistance vessels of the cerebral microcirculation. Mechanisms intrinsic to the vessel wall may play a significant role in the early stage of post-reperfusion hyperemia. Such mechanisms could also be implicated in other hyperemic phenomena affecting the cerebral circulation, such as the rapid increase in intracranial pressure after subarachnoid hermorrhage, the development of the normal perfusion pressure breakthrough phenomenon, and the initiation of intracranial pressure plateau waves.