Oral cancer remains an important global health issue and despite recent diagnostic and therapeutic advances, it continues to have an unfavorable prognostic and decreased survival. Although palatal tumors represent one of the rarest locations of oral squamous cell carcinomas (SCCs), they are among the most aggressive local tumors, leaving behind important morpho-functional disabilities. In order to explain such local aggressiveness, the present study aims to investigate the immunohistochemical expression in palate SCCs of some markers known to be involved in the process of tumor invasiveness, such as Wiskott-Aldrich syndrome like (WASL), Claudin-1 (CLDN1), Integrin beta-6 (ITGB6) and c-Mesenchymal to epithelial transition protein (c-Met). We have found here a higher tumor WASL and CLDN1 reactivity in well-differentiated (G1) palate SCCs, and regardless the histological type, degree of differentiation or tumor topography, an overexpression at the invasion front, and in those palate' SCC cases with muscular invasiveness and with lymph node (LN) dissemination. ITGB6 and c-Met had a higher reactivity in moderately differentiated (G2) palate SCCs, especially at the periphery of tumor proliferations, at the invasion front and in those high invasive cases and as well as in those that associated LN dissemination. All four investigated markers were also positive at the level of LN metastatic proliferations. None of the markers could statistically stratify on age group and pain, and on bone and perineural invasion while all of them statistically stratified on survival and grading. We concluded that these markers have a prognostic role allowing the identification of those cases with an unfavorable clinical evolution and decreased survival.