Oxidative stress is significant in numerous types of cancer. Tobacco smoke, an important risk factor for oral squamous cell carcinoma (OSCC), is able to generate reactive oxygen species (ROS) and cause oxidative DNA damage. Superoxide dismutase (SOD) is an endogenous antioxidant enzyme that is critical in limiting the oxidative burden effectively. The purpose of this study was to investigate the effects of the mitochondrial SOD2 and Cu/Zn enzyme SOD1 gene polymorphisms on the susceptibility to and clinicopathological characteristics of OSCC, as well as the synergistic effect between these gene polymorphisms and the well-known risk factor of tobacco consumption. Patients with clinically diagnosed OSCC (n=362) and healthy normal individuals (n=358) were investigated for four single nucleotide polymorphisms (SNPs; rs4880, rs5746136, rs1804450 and rs11556620) by polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing methods. Following adjustment for other confounders, no significant difference was observed in the rs5746136 SOD2 SNPs between the patients and controls. However, the incidence of the CT genotype of SOD2 SNP rs4880 was higher in the patients than in normal subjects in the additive model [CT vs. TT; P=0.045; adjusted odds ratio (AOR)=1.484; 95% confidence interval (CI), 1.009-2.182] and in the dominant model (CT/CC vs. TT; P=0.022; AOR=1.559; 95% CI, 1.067-2.278). For those who smoked, the incidence of the CT genotype of rs4880 increased markedly in the patients compared with the controls in the additive model (CT vs. TT; P=0.003; AOR=2.325; 95% CI, 1.330-4.064) and in the dominant model (CT/CC vs. TT; P=0.001; AOR=2.448; 95% CI, 1.417-4.230). For SOD1, polymorphisms at rs1804450 and rs11556620 were not present in any of the OSCC or control subjects. The results suggest that SOD2 rs4880 may be involved in the tumorigenesis of OSCC and may be useful as a genetic susceptibility marker for OSCC.