Cytochrome P450 (CYP) is a super family of mixed-function oxidases that are responsible for the human metabolism of drugs and endogenous compounds, as well as environmental and dietary substances. Many CYP enzymes function in the liver, but presence of CYP2E1 in the brain is demonstrating its role in both nicotine and ethanol metabolism. To examine the association between CYP2E1 polymorphism and the risk of oral cancer, we performed a case-control study on a south Indian population. 157 patients with oral cancer and 132 age and sexmatched controls were recruited. Three SNPs of the CYP2E1 gene [4768G>A (p. V179I, dbSNP rs6413419), CYP2E1_-1295G>C (dbSNP rs3813867) and CYP2E1_-1055C>T (dbSNP rs2031920)] were genotyped using TaqMan allelic discrimination. The V179I locus is monomorphic in the study subjects, whereas rs3813867 and rs2031920 are co-inherited with a minor allele frequency of 0.022. None of the polymorphic sites deviated from HWE in controls. A much lesser frequency of the uncommon c2 allele was seen in our control subjects than in Caucasians and East Asians. There were no significant differences between oral cancer and controls in the distribution of either allelic or genotype frequencies. None of the haplotypes showed a significant association with oral cancer. Our results suggest that CYP2E1 is not a major or independent determinant in the pathogenesis of oral cancer in south Indians.