Our study aims to determine the influence of smoking or tobacco chewing and the association of Interleukin 6 (IL-6) polymorphism, where G is substituted by A at the position - 596 (IL-6 - 596 G/A) and substitution of G by cytosine (C) at position - 572 (IL-6 - 572 G/C) on the susceptibility of precancerous oral lesions and oral cancer. The participants consisted of 250 subjects among which 75 were suffering from oral cancer, 75 subjects with precancerous oral lesions and 100 were healthy controls. Single-nucleotide polymorphism study (SNP) was done by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). IL-6 - 596 G/A SNP revealed genotypes, GG, and GA in subjects with precancerous oral lesions and oral cancer, and AA genotype was not found in any subject. IL-6 - 596 G/A was strongly associated with oral precancerous lesions but not with oral cancer. The present study reports that smokers carrying GA for IL-6 - 596 G/A were at several folds higher risk of developing oral precancerous lesions. Smokers with GC and CC for IL-6 - 572 G/C were at higher risk of developing oral precancerous lesions. No significant interaction was observed between these habits and IL-6 - 596 G/A and IL-6 - 572 G/C SNP with oral cancer. The interaction of variant A allele of IL-6 - 596 G/A and C allele of IL-6 - 572 G/C polymorphism with smoking and increases the risk of oral precancerous lesions. Tobacco chewing was not related with IL-6 - 596 G/A or IL-6 - 572 G/C in oral precancerous lesions or oral cancer. The study will help to determine the susceptibility of individuals with smoking or chewing habits to the development of oral precancerous lesion and oral cancer by monitoring the IL-6 SNPs which can be used as a biomarker for risk determination.