The prognostic significance of the expression of neural cell adhesion molecule (NCAM), a neuroendocrine antigen in lung cancer, was analyzed by an indirect immunoperoxidase method in 97 surgically treated patients. Reactivity of MOC-1 and S-L 11.14, both cluster-1 monoclonal antibodies directed against NCAM, was positive in all nine small-cell lung cancers and in 16 of 88 (18%) non-small-cell lung cancers. For the latter group, this expression demonstrated a phenotypic heterogeneity that was mainly observed in poorly differentiated squamous cell carcinomas and in stage N2 non-small-cell lung cancers. Patients with NCAM-positive non-small-cell lung cancer proved to have a shorter survival than those with NCAM-negative disease. In Cox's model for multivariate analysis, nodal status and histology were the main independent determinants of prognosis. We therefore concluded that NCAM expression in non-small-cell lung cancer is correlated to nodal status and that it indicates a poor prognosis. These findings confirm that the diversification of lung cancer phenotype leads to tumor progression and brings a negative prognosis to surgically resected non-small-cell lung cancer. However, nodal status remains the most important prognostic variable, suggesting that NCAM expression is only one of numerous biological events that promote tumor progression.