Oral Diseases(2010)16, 760–768Objectives: To examine role of genetic variants ofCYP2A13andUGT1A7genes, involved in activation and detoxification of tobacco carcinogens, with risk of head and neck cancer as well as to assess the potential modifying role of gene‐gene and gene‐environment interactions.Methods: 203 head and neck cancer patients and 201 healthy controls were genotyped for functional polymorphisms ofCYP2A13andUGT1A7genes using polymerase chain reaction‐restriction fragment length polymorphism, denaturing high‐performance liquid chromatography and sequencing.Results: We identified two novel polymorphisms T478C and T494C inCYP2A13gene which were associated with significantly reduced risk of cancer (OR 0.37; 95% CI 0.19–0.71;P < 0.05). ACYP2A13haplotype carrying variant alleles of T478C/T494C was found to be associated with reduced risk of head and neck cancer (OR 0.42; 95% CI 0.22–0.78;P = 0. 005). Mutant ‘T’ allele ofCYP2A13C578T polymorphism was found to be present in cancer patients only. A sevenfold increased risk of cancer was observed in smokers withUGT1A7low activity genotypes (OR 7.01; 95% CI 1.02–48.37;P < 0.05).UGT1A7haplotype carrying C allele (T622C) showed 10‐fold increased risk of cancer (OR 10.12; 95% CI 1.29–79.4;P < 0.05).Conclusion: Interplay between genetic variants ofCYP2A13andUGT1A7genes and smoking may modulate susceptibility to head and neck cancer.