Abstract Background Moesin is a member of the ERM (ezrin, radixin and moesin) proteins that participate in cell migration and tumor invasion through transductional signals sent to actin filaments by glycoproteins, such as podoplanin. Methods This study aimed to evaluate the participation of moesin and podoplanin in the invasive tumor front of oral squamous cell carcinomas, and their influence on patients’ prognosis. Podoplanin and moesin immunoexpressions were evaluated by a semi-quantitative score method, based on the capture of 10 microscopic fields, at 400X magnification, in the invasive tumor front of oral squamous cell carcinomas. The association of moesin and podoplanin expression with clinicopathological variables was analyzed by the chi-square, or Fisher’s exact test. The 5 and 10 years survival rates were calculated by the Kaplan-Meier method and the survival curves were compared by using the log-rank test. Results The immunohistochemical expression of moesin in the invasive front of oral squamous cell carcinomas was predominantly strong, homogenously distributed on the membrane and in the cytoplasm of tumor cells. The expression of moesin was not associated with clinical, demographic and microscopic features of the patients. Otherwise, podoplanin expression by malignant epithelial cells was predominantly strong and significantly associated with radiotherapy (p = 0.004), muscular invasion (p = 0.006) and lymph node involvement (p = 0.013). Strong moesin expression was considered an unfavorable prognostic factor for patients with oral squamous cell carcinomas, clinical stage II and III (p = 0.024). Conclusions These results suggested that strong moesin expression by malignant cells may help to determine patients with oral squamous cell carcinoma and poor prognosis.