A case control study was carried out to investigate the association of functionally important polymorphism in cytochrome P450 2A6 (CYP2A6) genes with head and neck squamous cell carcinoma (HNSCC) and treatment response in cases receiving a combination of chemo- radiotherapy. The study group consisted of 300 males suffering from HNSCC and an equal number of male controls. Multivariate logistic regression analysis revealed the frequency of the variant alleles of CYP2A6 were significantly higher in the controls when compared to the cases with the history of tobacco use. Also, , the frequency of the deletion variant alleles of CYP2A6*4C were significantly higher in the controls when compared to the cases with the history of alcohol consumption. These showed that the variant polymorphisms of CYP2A6 decreased the risk of HNSCC .Interestingly, only 37% of the cases carrying the variant forms of CYP2A6 responded to the treatment for HNSCC when compared to those with wild-type genotype (79%). Thus, it can be said that polymorphisms in CYP2A6 not only modified the risk to HNSCC but also played a major role in determining the chemotherapeutic response.