The aim of this study was to estimate the relations between hypoxia inducible factor-1alpha (HIF-1alpha) gene polymorphisms, C1772T and G1790A, to the susceptibility and clinicopathological status of oral cancer. A total of 521 subjects, including 347 controls and 174 oral cancer patients, were recruited in this study and subjected to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to analyze the impact of these two polymorphic variants on oral cancer. A significant association between oral cancer susceptibility and G1790A polymorphism was demonstrated since individuals with heterozygotes, that is GA, had a higher risk for oral cancer, compared to GG genotypes after adjusting for other confounders (AOR=3.31; 95%CI=1.27-8.61). Compared to individuals with both C1772C and G1790G homozygotes, individuals with at least one of either C1772T or G1790A of HIF-1alpha gene had a risk of 2.17-folds (95% CI=1.0-4.75) to develop oral cancer. Moreover, results also revealed the presence of synergistic effect between gene polymorphisms of HIF-1alpha and environmental risk factors, such as tobacco and betel nut consumptions while there was no significant association between HIF-1alpha gene polymorphism and clinicopathological parameters of oral cancer. Genetic polymorphism, including C1772T and G1790A, of HIF-1alpha is an important factor for the susceptibility to oral cancer.