ObjectivesTo evaluate the salivary detection of XRCC1 rs25487 single-nucleotide polymorphism (SNP), its relationship with clinicopathological characteristics, and the interactions with demographic/behavioral variables in the etiopathogenesis of oral potentially malignant disorders (OPMD) and oral squamous cell carcinoma (OSCC) in a Colombian population. MethodsDemographic/behavioral data and saliva samples were obtained from patients with oral leukoplakia (OL, n = 17) and oral lichenoid lesions with epithelial dysplasia (OLL-ED, n = 10), or OSCC (n = 45), along with healthy controls (n = 40). Tissue biopsies were obtained for histological assessment and genetic analysis was performed using polymerase chain reaction-restriction fragment length polymorphism. Descriptive analyses were used to compare the distribution of genotypes/alleles between study groups alongside an analysis of the interaction between genetic findings and demographic/behavioral variables. ResultsNo association was observed between the genotype and allele frequencies in OPMD or OSCC. The AG genotype was significantly more frequent in OL with high-grade dysplasia, acanthotic epithelial lining, moderate-to-severe mitotic count, and negative-to-mild apoptotic count; and in OSCC cases with stage III/IV, poorly differentiated, perineural/lymphovascular invasion, severe cellular atypia, moderate-to-severe mitotic count, and negative-to-mild apoptotic counts. Significant interaction effects were detected in the AG genotype with regard to ageing, smoking habits, and alcohol consumption in both OL and OSCC. ConclusionAlthough rs25487 SNP appeared to not modulate the risk of OPMD/OSCC independently, its significant association with clinicopathological characteristics in OL and OSCC, and the synergistic interaction between ageing and smoking/alcohol consumption, might play a role in these two diseases.