The epidermis is innervated by fine nerve endings that are thought to have important sensory functions including nociception. Their role in neuropathic pain is as yet unclear. We used rats with a chronic constriction injury (CCI) of the sciatic nerve, a model of painful partial nerve injury, to examine the temporal course of the epidermal innervation density in correlation with corresponding nerve fiber numbers in the sciatic nerve and with pain-related behavior of the rats. A significant reduction of protein gene product 9.5 (PGP 9.5)-immunoreactive (ir) fibers and a nearly complete loss of calcitonin gene-related peptide (CGRP)-ir fibers was found after CCI in the epidermis as well as in the sciatic nerve. Reappearance of epidermal fibers was delayed compared to the regeneration of nerve fibers in the sciatic nerve. The maximum of pain-related behavior occurred at the time of maximal reduction of epidermal nerve fiber density. Possible explanations for this apparent discrepancy could be the presence of abnormal electrophysiological properties in the few remaining epidermal fibers, the lack of inhibition by intact fibers, or the generation of hyperalgesia in deeper layers of the skin. The number of PGP 9.5-ir Langerhans cells was increased after CCI, and this increase also temporally correlated with the presence of thermal hyperalgesia and mechanical allodynia, supporting a role of Langerhans cells in the generation of pain.