Introduction: The CYP2E1 enzyme is responsible for the metabolic activation of several procarcinogens into reactive metabolites that result in carcinogenesis. The genetic polymorphisms that modify these enzymatic activities may be associated with upper aerodigestive tract cancer risk. Methods: This hospital-based study evaluated CYP2E1*1B, CYP2E1*5B and CYP2E1*6 polymorphisms in 408 histopathologically confirmed cases and 220 population-based controls using PCR-RFLP methods. Results: The multivariate logistic regression analyses demonstrated no significant differences between groups for all three polymorphisms when analyzed separately. However, the gene–environment interactions analyses revealed significant interactions among tobacco smokers (11–20 pack years), 20–40 pack years and >40 pack years), regular tobacco chewers and alcoholics carrying CYP2E1*1B mutant genotypes. Similarly, CYP2E1*6 polymorphisms resulted in significant interactions among tobacco smokers (>40 pack years) and regular tobacco chewers on the multiplicative scale. Conclusion: The significant gene–environment interactions observed for CYP2E1*1B and CYP2E1*6 polymorphic genotypes may confer a substantial risk for upper aerodigestive tract cancers among Indians.