Several lines of evidence have suggested that periodontal nerves have other roles besides sensory function. Exploring the distribution pattern of nerves in relation to other structures within the periodontal ligament of various species should be important to understand their roles within the ligament. This study investigated whether any association exists between the nerves and the epithelial cells in the periodontal ligament of continuously erupting guinea pig molars, which show distinct enamel epithelium layers among the cementum pearls. Ten guinea pigs were fixed by vascular perfusion and jaw sections were processed for immunohistochemistry of protein gene product 9.5 (PGP 9.5), growth-associated protein-43 (GAP-43) and glia-specific S-100 protein, and for enzyme histocytochemistry of cholinesterase. Nerves that were immunopositive for the above neuronal markers were located predominantly in the alveolus-related part of the periodontal ligament. Some nerves, immunoreactive for PGP 9.5 and GAP-43, were also found in the tooth-related part (TRP) of the periodontal ligament close to the tooth surface. PGP 9.5-positive nerves in the TRP appeared very thin and terminated by making loops or plexus-like structures in close apposition to the epithelium layers, overlying the enamel surface in between cementum pearls. Such an intimate association between nerves and the enamel epithelium was not found in the labial periodontal tissue of incisors or the apical growing end of the molar, where periodontal fibre attachment was indistinct. The association between nerves and epithelium in the periodontal ligament of guinea pig molar is site specific and is only seen in the presence of cementum, suggesting that this association is related to the attachment function of the ligament.