Genetic alterations in the genes expressing drug metabolizing enzymes can make an individual susceptible to various cancers. This study detects the polymorphisms at CYP1A1, GSTM1, and GSTT1 genes in a section of North Indian population and determines the susceptibility to oral submucous fibrosis (OSF). In this case-control study one hundred and two OSF patients were genotyped to detect the GSTM1, GSTT1, CYP1A1 polymorphism. Two hundred healthy controls were also included. Genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach. The frequency of GSTM1 and GSTT1 genotype was higher in OSF patients, as compared to controls. A trend risk analysis showed 7.6 fold increase in risk, when both the genes were absent. The frequency of CYP1A1 (m1) and CYP1A1 (m2) genotypes was higher in controls. No polymorphic alleles were detected in the m4 site. CYP1A1 (m1) wild genotype in the absence of GSTM1 null genotype, falls under the highest risk group (OR 3.74). Our findings suggest that CYP1A1 (m1) genotype and (m2) genotype singly acts as a protective factor but in the absence of GSTM1 and/or GSTT1 gene significantly alters risk towards OSF.