Using standard immunohistochemical techniques and an improved procedure for whole-mount vascular preparations, the authors describe the pattern and density of innervation of calcitonin gene-related peptide (CGRP)-like, neuropeptide Y (NPY)-like and vasoactive intestinal polypeptide (VIP)-like immunoreactivity in major arteries of postmortem adult human circles of Willis. Calcitonin gene-related peptide-, NPY-, and VIP-LI exhibited a variety of varicose and nonvaricose single axons, and small and large perivascular nerve bundles. Although the density of innervation within each vascular segment was highly variable, the pattern of innervation for each neuropeptide observed was consistent throughout the circle of Willis. With the use of human and rat circles of Willis as positive control preparations, the lack of CGRP-LI, NPY-LI, and VIP-LI in vessel segments taken from five cases of intracranial arteriovenous malformations (AVMs) is also reported. It is concluded that adult human circles of Willis exhibit CGRP-LI, NPY-LI, and VIP-LI perivascular nerves. In addition, intracranial AVMs do not possess these peptide-containing nerves that, in animals, normally mediate neurogenic control in the cerebrovasculature. It is hypothesized that this lack of innervation, and hence neurotrophic influence, may contribute to the development of AVMs.