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Aims: This study examined whether genetic polymorphisms of tobacco and alcohol-related metabolic genes such as GSTM1, GSTT1, GSTP1, CYP1A1, CYP2E1 and DNA repair genes (XRCC1 194Trp, XRCC1 399Gln, and XRCC3 Met) contribute to the risk of developing OSCC. Methods: Patients eligible for inclusion were over 18 years, had pathologically confirmed OSCC and were followed prospectively for at least two years or until death, from December 2000 to December 2004. Ninety-two OSCC patients were included along with 244 subjects from the same hospital, evaluated in the same period as patients without cancer, as the control group. Results: GSTM1 null and XRCC1-194Trp alone increased the risk of OSCC (OR, 2.15; 95% CI, 1.2 - 3.6 and OR, 2.02; 95% CI, 1.01 - 4.03, respectively). The joint effect of GSTM1 null with CYP1A1 or CYP2E1 polymorphism increased the risk two to threefold. Similar results were observed when XRCC1-194Trp was combined with GSTM1 null or the CYP2E1 polymorphism. By contrast, XRCC1- 399Gln was associated with protection against OSCC. Gene-gene and gene-environmental interactions were mainly detected for CYP1A1 and GSTP1 associated with more than 20 p/y of tobacco and XRCC1-194Trp when more than 30 g/L/d of alcohol was consumed (OR, 8.8; 95% CI; 1.3 - 45.7). Conclusions: The drug metabolizing and DNA repair enzyme polymorphisms may be informative for clinicians in the preventive management of patients at risk, particularly those with strong smoking and drinking habits.