Many if not most epidermal Langerhans cells appeared to be closely associated anatomically with calcitonin gene-related peptide (CGRP)-containing nerves as determined by confocal laser scanning microscopy. Furthermore, a small proportion of Langerhans cells had immunoreactive CGRP at or near their cell surfaces, suggesting that nerves are capable of depositing CGRP at or near Langerhans cells. CGRP inhibited Langerhans cell antigen-presenting capability for elicitation of delayed-type hypersensitivity in immunized mice to present alloantigens in the mixed epidermal cell-lymphocyte reaction and to present a protein antigen to a responsive hybridoma. As a whole, these data suggest the possibility that products of nerves within the epidermis might serve to regulate Langerhans cell function. The apparent apposition of epidermal nerves with Langerhans cells suggests a possible locus of interaction between the nervous system and the immune system within the skin.