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Xenobiotic metabolic enzymes CYP1A1 and GSTM1 are known to increase the risk of head and neck cancer. However, their role in the development of oral potentially malignant disorders (OPMDs) in the Indian population is uncertain. This study aimed to investigate the CYP1A1 and GSTM1 gene polymorphism in the urban population of the state of Delhi as well as to investigate the risk of disease progression. Genotype analysis via polymerase chain reaction was conducted in 1169 cases and 1046 controls with regard to GSTM1 and CYP1A1 (ile-val) genes. The oral lesions were biopsied for histopathological diagnosis. Follow-up of the subjects was done at 6-month intervals and the status of the lesions was recorded as static, progressed, or regressed. Descriptive analysis was done with a p-value ≤ 0.05 and odds ratio with a 95% confidence interval being considered for a measure of association. Subjects who consumed both tobacco and alcohol and developed OPMD lesions were 8.2 times more likely to harbour CYP1A1 Val/Val genotype (p = 0.047; OR = 8.224; 95% CI = 1.024–66.037). The highest progression rate and lowest regression rate were found for the CYP1A1 Val/Val genotype in our sample. The CYP1A1 Val/Val genotype may be associated with an increased risk of development of OPMDs amongst consumers of both tobacco and alcohol. Real-time activity-based sensing of isoforms of the CYP1A1 enzyme in living systems is needed to validate the same. [ABSTRACT FROM AUTHOR]