Currently, tongue squamous cancer appears to be more frequent, especially among adults under the age of 45. Approximately 50% of these patients are diagnosed late, with clinically detectable metastases; the five-year survival rate of patients with loco-regional metastases is less than 60%. In order to explain this behavior, many investigations have been conducted in recent years, most of them focusing on identification of potential prognostic and therapeutic markers involved in the pathogenesis of tongue cancers. Our research follows the same trend, which aims to study the prognostic implications of immunohistochemical (IHC) expression of markers C-X-C chemokine receptor type 4 (CXCR4), matrix metalloproteinase (MMP)-2 and MMP-9 in 54 cases of tongue squamous carcinoma. The cases were selected from the archives of the Laboratory of Pathology, Emergency County Hospital, Craiova, Romania, from the 2015-2017 period. They were immunohistochemically processed using the labeled Streptavidin-Biotin (LSAB) enzyme detection technique, and as a method of evaluating reactions, the IHC score developed by Remmele & Stegner. Reactivity for the investigated markers was recorded in both primary tumors, parenchymal and stromal, and in lymph node metastases, and also in normal or dysplastic mucosa adjacent to tumor lesions. The maximum tumor reactivity was recorded for CXCR4, followed by MMP-9 and MMP-2. In addition, all of these markers were expressed stronger in the invasion front and especially in the lymph node metastatic forms. This immunoprofile would suggest their implication in loco-regional invasion and dissemination processes, allowing the selection of the most aggressive forms of tongue squamous carcinoma.