Oral cancer is the major cause of mortality and morbidity worldwide. There are many factors that influence the tumor microenvironment that promotes tumorigenesis. Hypoxia is one of the factors that affects the process of angiogenesis by inducing proangiogenic factors to maintain the blood supply which in turn enhances the aggressiveness of the tumor and prognosis of solid tumors such as oral squamous cell carcinoma. The aim of the study was to compare the expression of hypoxia-inducible factor 1α (HIF-1α) and hypoxia-inducible factor 2α (HIF-2α) in various histological grades of oral squamous cell carcinoma immunohistochemically. Immunohistochemical evaluation of HIF-1α and HIF-2α was done in 90 samples of oral squamous cell carcinoma which were graded histologically into 30 samples each of well, moderately and poorly differentiated squamous cell carcinoma. Statistical evaluation: Statistical analysis was doneto study the prognostic significance of the biomarkers. All the cases showed positivity for expression of HIF-1α and HIF-2α. The number of positive staining in both markers reduced as the tumor severity increased from well to poorly differentiated. The expression of MIL of HIF-2αwas higher than HIF 1α and HIF 2α expression was mostly seen in cytoplasmic in well-differentiated and nuclear in both moderately and poorly differentiated OSCC suggestive that HIF-2α is a more specific marker to hypoxia. Hypoxia is an essential factor that triggers other angiogenic switch and inflammatory factors which facilitates the process of tumorigenesis. This is also important for predicting the treatment outcome and prognosis of the patients. HIF-2α is a more sensitive marker that appears to be correlated and could perhaps serve as a good surrogate marker of hypoxia.