Gene-gene interaction analysis by multifactor dimensionality reduction (MDR) revealed that XRCC3Thr 241 Met had the largest univariate effect followed by XRCC3Thr 241 Met - NAT2 A857G in men that presents a highly synergistic interaction as one of the potential combinations of single nucleotide polymorphisms (SNPs) to increase the risk of OSF in men if exposed to arecanut or smokeless tobacco usage.