Studies were undertaken in Long Evans rats to examine the hypothesis that chronic unilateral sectioning of vasodilating nerve fibers (parasympathetic and/or sensory) innervating the circle of Willis increases infarction volume following unilateral branch occlusion of the middle cerebral artery (MCA) combined with temporary (45 min) bilateral common carotid occlusion. Infarct size was measured 24 h after surgical occlusion from seven coronal slices. Infarction volume (mean +/- SD) in sham animals (group A) and surgically naive animals (group B) measured 153 +/- 43 and 131 +/- 38 mm3, respectively. After lesions of both sensory (nasociliary nerve) and parasympathetic efferents at the ethmoidal foramen (group C, combined lesion) or selective lesions of parasympathetic efferents (group D), infarction volume increased [214 +/- 47 mm3 (p less than 0.01) and 209 +/- 46 mm3 (p less than 0.05), respectively]. No increases were detected after cutting the nasociliary nerve alone (group E) or occluding the external ethmoidal artery (group F) [145 +/- 39 mm3 (p greater than 0.05) and 124 +/- 63 mm3 (p greater than 0.05), respectively]. The infarct was predominantly located within cortical gray matter and became enlarged on its superior and inferior aspects after parasympathectomy. Large infarcts were noted whether animals breathed spontaneously (all of the above) or were artificially respired or whether animals were anesthetized with xylazine and ketamine or chloral hydrate. Taken together, these studies suggest a previously unrecognized protective role for autonomic parasympathetic fibers in the pathophysiology of focal cerebral ischemia that is not shared by sensory fibers. The importance of autonomic vasodilating fibers to blood flow in ischemic brain merits further study.