Perineural invasion (PNI) is the underestimated metastatic pathway and has been widely recognized as a negative prognostic factor in many human cancers. L1CAM is one of members of the immunoglobulin-like cell adhesion molecule (CAM) family, which play a role in neural development. Moreover, a new role of L1CAM outside the nervous system has been revealed. Overexpression of L1CAM was involved in the tumor progression and LN metastasis in various malignancies. In the present study, presence of PNI and L1CAM expression were examined to define their prognostic values in OSCC. In addition, association of L1CAM expression with presence of PNI was assessed to define the value as a candidate molecule supporting the diagnosis of PNI. We found that presence of PNI significantly correlated with LN metastasis and advanced clinical stage. L1CAM expression also significantly correlated with differentiation, lymph node metastasis, advanced clinical stage, as well as presence of PNI. Our results suggest that L1CAM seems to play a role in tumor progression, possibly through the PNI-related mechanism and could be a molecular marker for supporting the presence of PNI and predicting clinical outcome in OSCC.