Oral cancer is known to progress through well characterized premalignant lesions that include leukoplakia, erythroplakia, lichen planus and submucosal fibrosis, all of which have the potential to transform into squamous cell carcinoma with varying rates of risk. The contributory role of an angiogenesis in the development and sustenance of neoplastic growth is well established, however the correlation in premalignant lesions has not yet been clearly defined. In frank malignancy, the process of new vessel formation is stimulated by the expanding tumor’s increasing demand for nutrients and oxygen. The ability of cancer stem cells (CSCs) to maintain their capacity for self-renewal, pluripotency, and potential for tumor initiation depends on the presence of a supportive perivascular niche. Microvascular density has been found to correlate to the presence of CSC niche in overt carcinoma of the head and neck. In order to evaluate the relationship between MVD and CSC and their correlation to the dysplasia characteristics, we evaluated their profile in pathologically distinct and progressive stages of oral cancer. Patients with oral cancer (N=262) were histologically examined and categorized into normal, non-dysplastic or with mild, moderate, or severe dysplasia and carcinoma for the study. Immunohistochemical analysis was carried out for D31, an endothelial marker, and CD44, a cancer stem cell marker in these cohorts. Tissues with non-dysplastic, mild, moderate, and severe dysplasia demonstrated MVDs of 11 +/- 1.4/hpf, 12.23 +/-0.91/hpf, and 13.5 +/-1.068/hpf respectively. A further classification of the patient cohorts into low risk and high risk group showed a significant difference in the MVD (Low risk: 11.61 +/-0.61; High risk: 13.58+/-0.10; p=0.0051). Assessment of the CD44 immunohistochemical profile with the different patient cohorts indicated a significant increase in expression in the high risk samples (115+5.24) when compared to the normal cohort (67+12.03, p=0.01) and low risk cohort (74+3.34, p=0.0001). A correlation of the expression pattern of both the CD44 and CD31 indicated that CD31high/CD44high cohort had the highest percentages of high risk (41%) and carcinoma (31%) as compared to the CD31low/CD44low group (high risk:13% and Low risk: 20%). Notably, CD31 expression alone (CD31high/CD44low) did not correlate with the grades of dysplasia while CD44 expression (CD31low/CD44high) did show a correlation (normal: 0%; low risk: 4%; high risk: 14%; carcinoma: 24%). Given this finding, microvascular density expressed in concordance with the CSC cells may be a significant marker of malignant progression, establishment of its clinical applicability warrants further investigations.