Mel-CAM (CD146) is a cell-cell adhesion protein found in normal and tumoral tissues. The aim of this study was to analyse Mel-CAM expression in mucoepidermoid carcinoma (MEC), and assess its importance in prognosis and its utility in differentiating high-grade MEC from squamous cell carcinoma (SCC). Immunohistochemical expression of Mel-CAM in 41 parotid MEC was correlated with clinical parameters. Ten cases of oral cavity SCC were included for comparison. Mel-CAM expression was found in 92.7% of the MEC but was not expressed by the SCC. Mel-CAM expression was greater in intermediate/high grade tumors, was weaker in patients that presented local recurrence, regional and distant metastasis, but no correlation between Mel-CAM and clinical stage and survival of the patients was found. Decreased Mel-CAM expression can impair cellular contact properties, facilitating growth, cell spreading and metastasis in MEC. Mel-CAM can also be useful in differentiating high grade MEC from SCC.