Tobacco-related oral squamous cell carcinoma is a common malignancy in Asian people. It accounts for almost 40% of cancers among Indian men and 3% in the Western world. Smokeless tobacco has been shown to induce tumor necrosis factor-alpha (TNF-alpha), which, along with its receptors, is over-expressed in people with oral carcinoma. Single nucleotide polymorphisms (SNPs) in TNF-alpha and TNF receptor genes may affect their expression and may be a potential determinant of susceptibility to tobacco-related oral carcinomas. We assessed SNPs in TNF-alpha(-308, -238) and TNF receptor 1 (TNFR1; -609) promoters by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and at four sites of TNF receptor 2 gene (TNFR2; exon 9 site 1176; exon 10 sites 1663, 1668 and 1690) by PCR-sequence-specific primers (PCR-SSP) techniques, respectively, in 94 patients and 130 healthy controls. TNF-alpha-308 G allele was significantly lower (Pc=0.004; OR=3.85), whereas A allele was significantly higher (Pc=0.004; OR=0.25) in patients compared with controls. No significant change was observed at -238 promoter site between the two groups. In the case of TNF receptors, both TNFR1 -609 TT (Pc=0.006; OR=15.3) and TNFR2 1690 CT (Pc=0.018; OR=5.6) genotypes were significantly lower in patients compared with controls. It seems that TNF-alpha-308 G/A may be related to susceptibility, whereas -609 TT TNFR1 and 1690 C/T TNFR2 SNPs may be protective to tobacco-related oral squamous cell carcinoma. These SNPs may be useful as a marker for high-risk groups among Asian Indians.