Differences in genetic susceptibility to tobacco-induced carcinogenesis appear to modulate an individual's risk of squamous-cell carcinoma of the head and neck (SCCHN). Risk for SCCHN may be associated with the null alleles of the carcinogen-metabolizing genes glutathione-S-transferase (GST) T1 and GSTM1. In this study, we evaluated the association between GSTM1 and GSTT1 null genotypes and risk of SCCHN in a matched case-control study of 162 patients with SCCHN and 315 healthy controls. Our results showed that 53.1% of cases and 42.9% of controls were null for GSTM1, whereas 32.7% of cases and 17.5% of controls were null for GSTT1 (p < 0.05 and p < 0.001, respectively). Furthermore, 19.8% of cases but only 7.9% of controls were null for both genes (p < 0.001). Multivariate analysis using logistic regression models, including age, sex, ethnicity, smoking status, alcohol status and GST genotypes, showed that both of these genotypes remained independent risk factors for disease [adjusted odds ratios (ORs) = 1.50 and 2.27, respectively; 95% confidence intervals (CIs) = 1.01-2.23 and 1.43-3.60, respectively). When the genotypes were divided into neither null, either null or both null, there was a dose-response relationship (adjusted OR = 1.50, 95% CI = 0.98-2.30) for the either-null group and (adjusted OR = 3.64, 95% CI = 1.94-6.84) for the both-null group (p < 0.001, trend test). Our findings suggest that the GSTM1 and GSTT1 null genotypes are independent risk factors for SCCHN and markers for genetic susceptibility to tobacco-induced carcinogenesis.