Investigations of the ability of polymorphisms in the GSTM1, GSTT1, and GSTP1 genes to alter susceptibility to head and neck squamous cell carcinoma (HNSCC) have examined gene-environment interaction in their detoxification of tobacco-associated carcinogens. Little work has been done to ask if these variant genes also modify the interaction of tobacco and alcohol in the development of HNSCC. To test this hypothesis, we conducted a case-control study, enrolling 692 incident cases of HNSCC and 753 population controls. Information about lifetime tobacco and alcohol use was ascertained through questionnaires, and genotypes for GSTM1, GSTT1, and GSTP1 were determined from constitutional DNA. Genotype frequencies were compared among cases and controls, and the association between genotypes and tobacco use was evaluated on cancer risk through logistic regression. Deletion of GSTM1 was associated with an increased risk for HNSCC [odds ratio (OR), 1.3; 95% confidence interval (95% CI), 1.0-1.6]. GSTT1 deletion was associated with a slight decreased HNSCC risk (OR, 0.8; 95% CI, 0.6-1.0). Among those with GSTM1 present, the OR of cancer for heavy smoking was 2.6 (95% CI, 1.6-4.3) compared with 4.2 for those with the GSTM1 deleted (95% CI, 2.6-6.7). The combination of consuming 10 to 20 alcohol drinks weekly and smoking >45 pack-years was associated with a 13-fold elevated risk (OR, 12.6; 95% CI, 4.0-40.2) among the GSTM1 deleted subjects compared with an OR of 3.6 (95% CI, 1.5-8.7) among the GSTM1 present individuals. These data (showing that the GSTM1 deletion affects on the tobacco and alcohol synergy) suggest that the interaction of these carcinogens is, at least in part, driven by alcohol, enhancing the carcinogenic action of tobacco smoke.