Background: The American Joint committee on Cancer in their 8th edition staging manual regarded perineural invasion as one of the most important prognostic factors for Lip and Oral Cavity Squamous Cell Carcinoma, it also incorporated tumor depth of invasion in defining tumor size category in the new staging system. This study was conducted to evaluate the frequency of perineural invasion in oral squamous cell carcinoma and the effect of approaching tumor depth in this process. Materials and Methods: fifty-four formalin fixed paraffin embedded tissue blocks of radical resections of Oral Squamous Cell Carcinoma were cut and stained with Hematoxylin and Eosin stain, then evaluated for perineural invasion, with estimation of tumor depth of invasion for each case. Results: Perineural invasion was found in twenty-two cases of the study sample. The diameter of the largest nerve bundle that showed perineural invasion was found to have a positive significant correlation with tumor depth of invasion (p=0.025). Perineural invasion status in terms of (present, absent) showed a significant difference with patients’ age (p=0.037), also showed a significant association with tumor site (p=0.004), however, this association was non-significant in regard to tumor grade and stage (p=0.848, p=0.520) respectively. Conclusion: The attacking potential of preceding tumor depth and those cancers affecting young individuals may be reflected by the presence of neural infiltration by tumor cells. Tongue resected tumors should be carefully inspected for this deceptive biological process.