Molecular epidemiological studies have provided evidence that individual susceptibility to cancer is mediated by both genetic and environmental factors. Several allelic variants of polymorphic glutathione s-transferases (GSTs) show impaired enzyme activity and are suspected to increase the host’s susceptibility to various cancers. To determine the association of GST variants with the risk of oral submucous fibrosis (OSF), the distribution of polymorphisms in GSTM1 and GSTT1 was studied in 90 OSF patients and 130 healthy controls. Genotypic analysis was performed by multiplex PCR. The relationship between the null genotypes and the risk of OSF was assessed by means of odds ratios (OR) with 95% confidence intervals (CI) calculated by logistic regression. The frequency of both the GSTM1 and GSTT1 null genotypes was higher in the OSF cases than in the controls. The prevalence of the GSTM1 null genotype in the OSF cases was 46.6% as compared to 29.2% in the controls (OR 2.12, 95% CI 1.2–3.9) and GSTT1 null was 24.4% in the OSF cases versus 10.7% in the controls (OR 2.68, 95% CI 1.22–5.96). There was evidence of an increased risk with the absence of both genotypes (7.5-fold; OR 7.5, 95% CI 2.3–24). Our findings suggest that the GSTM1 and GSTT1 null genotypes, separately or in combination, increase the risk of developing OSF in the North Indian population.