Squamous cell carcinoma (SCC) of the oral cavity is the most frequent epithelial neoplasm among head and neck cancers, with multifactorial etiology. Risk factors include smoking, alcohol consumption, and genetic predisposition. The p53 gene, known as the guardian of the genome, has a polymorphism at codon 72 of exon 4, resulting in the arginine/proline genotype. This case-control study included 280 healthy individuals and eight patients with oral SCC treated at a reference hospital in Brasília. Using PCR-RFLP, we investigated the association between the p53 Arg72Pro polymorphism (rs1042522) and oral SCC. A statistically significant predominance of the Arg/Arg genotype was observed in the case group (p=0.004). The results suggest that the Arg/Arg genotype may be associated with an increased risk of developing oral SCC. It is concluded that, although promising, studies with larger samples are needed to validate this polymorphism as a predictive marker.