Both genetic and environmental factors are involved in the development of cancer; some phase I and II enzymes involved in the metabolism of carcinogens are polymorphic in genotypes. This case-control study focused on the interactions between oral cancer risk factors and genetic polymorphisms of cytochrome P-450 (CYP) 2E1 and glutathione S-transferase (GST) M1 and GSTT1. A total of 41 male oral cancer cases was recruited from National Taiwan University Hospital, and 123 healthy controls frequency-matched on ethnicity, sex, and age were recruited from residents living in Taipei City and Taipei County. History of cigarette smoking, alcohol drinking, and betel quid chewing was obtained through a standardized questionnaire interview, and genotypes of CYP2E1, GSTM1, and GSTT1 were determined by PCR. Cigarette smoking, alcohol drinking, and betel quid chewing were significantly associated with the risk of oral cancer in a dose-response relationship. All betel quid chewers smoked cigarettes in both the case and control groups. In the multiple logistic regression analysis, those who had null genotypes of GSTM1 and/or GSTT1 had an increased oral cancer risk compared with those who had non-null genotypes of both GSTM1 and GSTT1, showing a multivariate-adjusted odds ratio (OR) of 4.6 with a 95% confidence interval (CI) of 0.9-23.7 (P = 0.08). The CYP2E1 c1/c2 and c2/c2 genotypes were associated with a significantly increased oral cancer risk compared with the c1/c1 genotype among those who did not chew betel quid (OR, 4.7; 95% CI, 1.1-20.2), but not among betel quid chewers. Habitual alcohol drinking was associated with a significantly increased oral cancer risk, showing an OR of 3.0 (95% CI, 1.1-8.8). These results implied that there are gene-gene and gene-environment interactions in the development of oral cancer.