Port-wine stains result from a progressive ectasia of the cutaneous superficial vascular plexus. One hypothesis for the pathogenesis of this lesion is an abnormal neural regulation of blood flow. Biopsy specimens of 11 port-wine stains, seven hemangiomas, and 17 benign lesions were stained for S100 protein using immunoperoxidase techniques. All specimens were of facial biopsies or excisions and were evaluated for vessels per square millimeter, nerves per square millimeter, vessel-to-nerve ratio, and frequency of vessels coursing within 0.03 mm of nerves. These variables were evaluated in the superficial 0.8 mm of dermis, a zone that includes almost all abnormal port-wine-stain vessels. Controls showed 18.3 +/- 2.8 vessels/sq mm (+/- SD), 21.1 +/- 9.2 nerves/sq mm, 0.9 +/- 0.3 vessels to nerves, and 75% +/- 11% of vessels coursing within 0.03 mm of nerves, values that did not alter with age. Port-wine stains had a significant decrease in nerve density and increase in vessel-to-nerve ratio when compared with normal skin; only 17% +/- 3% of vessels were associated with nerves in port-wine stains. These findings document a deficit in the number of perivascular nerves in port-wine stains and raise the possibility that a lack of neural modulation of vascular flow may be involved in the pathogenesis of port-wine stains.