As oxidative stress is implicated in the pathogenesis of head and neck squamous cell cancer (HNSCC), the functions of antioxidant enzyme systems and DNA repair proteins are critical in the development of cancer. To investigate the role of genetic polymorphisms of the antioxidant superoxide dismutase 2 (SOD2) Val16Ala, glutathione peroxidase 1 (GPX1) Pro198Leu, and the DNA repair Xeroderma Pigmentosum Group D (XPD) Lys751Gln genes under exogenous risk factors, including smoking and alcohol consumption, in HNSCC carcinogenesis, we conducted a case-control study on 139 unrelated cases and 265 non-cancer controls. Polymorphisms were analyzed in additive, dominant and recessive genetic models, individually and in an interaction model. Carriers of the T allele of SOD2 were associated with an increased risk for HNSCC in the overall subgroups of males and smokers; similarly, the T allele of GPX1 was associated with elevated risk in the overall and smoker subgroup. A 12.47-fold increased risk was observed for the carriers of GPX1 TT, SOD2 CT and XPD CC genotypes for HNSCC. This is the first study presenting the potential roles of SOD2, GPX1 and XPD polymorphisms in interaction and under three genetic models in the development of HNSCC. The results suggest that these polymorphisms slightly modify the risk in HNSCC development individually but are significantly higher when they functioned and were evaluated together.