Carcinoma cell detachment is an important step in tumor progression and metastasis. Episialin (EMA), if expressed throughout the entire cell surface, may inhibit cell-cell and cell-matrix adhesion. We investigated whether the cellular distribution of episialin in non-small cell lung cancer (NSCLC) is associated with tumor progression. We evaluated the expression of episialin by immunohistochemical staining, in surgical specimens from 122 adenocarcinomas and 99 squamous cell carcinomas. Episialin was present in most NSCLC, with a higher percentage of immunoreactive neoplastic cells in adenocarcinoma than in squamous cell carcinoma (p = 0.0001). In adenocarcinoma the depolarized pattern was significantly associated with nodal metastasis (p = 0.005) and with advanced stage (p = 0.007). In conclusion, nodal metastasis and advanced pathological stage in adenocarcinoma are associated with a depolarized cellular distribution of episialin, suggesting a possible involvement of the molecule in cancer metastasis.