Altered postictal cerebral blood flow dilatory responses may contribute to brain injury following neonatal seizures. We developed an initial series of experiments to characterize the effects of seizure activity on cerebral vascular dilatory responses during the immediate postictal period. Significant attenuation of postictal hypoxic cerebral vasodilation was noted. We hypothesize that this diminished cerebral dilator response to hypoxia involves depletion of adenosine (Ado) activity resulting from seizure ictus. Additional experiments were designed to evaluate whether the altered postictal responses were related to a depletion of Ado stores or a decreased response to Ado in the postictal state. Farm-bred piglets were equipped with closed cranial windows. Responses to hypercapnia (10% CO₂), hypoxia (fractional inspired O₂ = 0.10), and topical sodium nitroprusside (10⁶ M) were compared before and after bicuculline-induced seizures (1 mg/kg). Hypoxia-induced cerebral vasodilation was significantly attenuated in the first 90 min postictal (control: 56.5 ± 6%, 10 min postictal: 6.3 ± 2%, 60 min postictal: 21.7 ± 6%, and 90 min postictal: 21.6 ± 5%; P < 0.01), whereas the dilator responses to hypercapnia and topical sodium nitroprusside remained intact. In a separate group of piglets, both a dilating (10⁵ M) and a nondilating concentration of Ado (10¹¹ M) were topically administered postictally to measure their effects on pial vessel dilatory response to hypoxia. Dilation to topical Ado (10⁵ M) was not altered postictally compared with control. Ado (10¹¹ M) restored hypoxia-induced vasodilation to preseizure control values in the immediate postictal period (control: 51.0 ± 8%, postictal: 46.7 ± 8%; P > 0.05). Postictal administration of Ado will restore hypoxia-induced cerebral vasodilation in piglets even when a nondilating concentration is employed. This suggests that depletion of Ado with seizure activity is a mechanism for the loss of postictal cerebral vasodilation to hypoxia, and the role of Ado in hypoxic cerebral vasodilation is permissive.