Perineural spread (PNS) is a poor prognostic factor associated with increased risk of local recurrence and nodal metastasis and reduced survival of patients with squamous cell carcinoma of the head and neck (SCCHN). There is some evidence to indicate that neural cell adhesion molecules (NCAMs) may play a role in PNS of a variety of tumor types. We performed this study to investigate whether NCAM expression can be used as a predictor of PNS in SCCHN. The surgical specimens of 66 patients with SCCHN were evaluated with monoclonal IgG antibody immunoperoxidase staining for NCAM. Of the 41 specimens with PNS, 38 (93%) showed evidence of NCAM expression. In contrast, only 9 specimens (36%) without PNS expressed NCAMs. The difference in NCAM expression between the study and control groups was statistically significant (P < 0.01).