Background: Tobacco and alcohol contain or may generate carcinogenic compounds related to cancers.CYP1A1 enzymes act upon these carcinogens before elimination from the body. The aim of this study was toinvestigate whether CYP1A1 T3801C polymorphism modulates the relationship between tobacco and alcoholassociatedhead and neck cancer (HNC) susceptibility among the northeast Indian population. Materials and Methods: One hundred and seventy histologically confirmed HNC cases and 230 controls were included withinthe study. The CYP1A1 T3801C polymorphism was determined using PCR-RFLP, and the results were confirmedby DNA sequencing. Logistic regression (LR) and multifactor dimensionality reduction (MDR) approaches wereapplied for statistical analysis. Results: The CYP1A1 CC genotype was significantly associated with HNC risk(P=0.045). A significantly increased risk of HNC (OR=6.09; P<0.0001) was observed in individuals with combinedhabits of smoking, alcohol drinking and tobacco-betel quid chewing. Further, gene-environment interactionsrevealed enhanced risks of HNC among smokers, alcohol drinkers and tobacco-betel quid chewers carryingCYP1A1 TC or CC genotypes. The highest risk of HNC was observed among smokers (OR=7.55; P=0.009)and chewers (OR=10.8; P<0.0001) carrying the CYP1A1 CC genotype. In MDR analysis, the best model forHNC risk was the three-factor model combination of smoking, tobacco-betel quid chewing and the CYP1A1variant genotype (CVC=99/100; TBA=0.605; P<0.0001); whereas interaction entropy graphs showed synergisticinteraction between tobacco habits and CYP1A1. Conclusions: Our results confirm that the CYP1A1 T3801Cpolymorphism modifies the risk of HNC and further demonstrated importance of gene-environment interaction.