The purpose of the present study was to examine the pial arteriolar diameter and evoked vascular responses after single episodes of cortical spreading depression (CSD) in rats and cats in order to elucidate the mechanisms of the persistent change of cortical perfusion which succeeds CSD. This problem is of potential clinical interest also since CSD may be involved in migraine pathophysiology. Using an open cranial window technique, pial arteriolar diameterswere measured with an image splitting method. Vascular reactivity was tested by local perivascular microapplication of mock cerebrospinal fluid (CSF) containing high and low levels of K⁺, high and low pH, adenosine and bradykinin before and after CSD which was triggered by intracortical injection of KCl. During CSD a monophasic vasodilatation of 26.0 ± 3.7% (mean ± S.E.M.; cat) or 64.6 ± 3.9% (rat) was observed. Following CSD, the cat developed persistent vasodilatation (16.7 ± 1.9%) while the rat exhibited vasoconstriction (12.1 ± 1.8%). Both species displayed a severely impaired responsiveness to constrictor and dilating stimuli as compared to pre-CSD values. The responses were reduced by 28-84%, dependent on the substance tested. It is concluded that vascular reactivity is severely impaired after CSD (15-75 min) and that this might explain the impaired coupling between flow and metabolism after CSD.