The distribution of nerve fibers containing either calcitonin gene-related peptide (CGRP) and substance P (SP) was investigated in rat skin with special reference to their relationship to the lymphatic vessels. These nerve fibers exhibited a similar distribution pattern but the former were more numerous than the latter. In the dermis and subcutaneous layers, thin nerve fibers containing CGRP or SP were in abundance, and were observed running along the blood vessels as well as freely in the tissue. Nerve fibers with these peptides were often located close to lymphatic capillaries, and innervated lymphatic vessels in the subcutaneous layer, reaching smooth muscles of the tunica media. These findings suggest that some CGRP and SP may directly drain into lymphatic vessels when released under noxious stimulation from nerve fibers around the lymphatic vessels. When discharged from nerve fibers in the vicinity of blood vessels, both peptides may also drain into the lymphatic vessels after causing blood vascular dilation and an increase in permeability producing edema. These peptides may then be transported to the draining lymph nodes where they can modulate the functions of the immune system.