Background: Oral cancer is one of the common cancers in India with dismal survival in advanced stages. Most of the patients present in advanced stages with borderline operability and such patients may be helped by chemotherapy to render them operable. It is well known that tumor growth is angiogenesis-dependent and thus vascular endothelial growth factor (VEGF) may be a surrogate marker of growth and angiogenesis. At present, there is a scarcity of predictive markers for oral cancer. In this prospective study, we studied VEGF expression and its role as a predictive marker in oral cancer. Materials and Methods: Patients with locally advanced oral cancer having borderline operability or unfit to undergo surgery in the primary setting were included in the study. VEGF expression of the cancerous tissue was studied in all patients. Three cycles of neoadjuvant chemotherapy (NACT) was administered before definitive treatment in locally advanced cases and response is assessed. VEGF levels were analyzed in cancer tissue and compared with normal surrounding mucosa. The response to chemotherapy was then correlated with VEGF score in patients receiving NACT to evaluate it as a predictive marker. Results: All forty patients were VEGF-positive and had a mean score of 1023 with 63% patients having Grade 3 expressions, whereas the normal surrounding mucosa had a VEGF score of 30. It was seen that in patients showing no response to treatment, the mean total VEGF score was significantly higher as compared to those showing complete or partial response. VEGF score correlated inversely with chemotherapy response, but no significant association was seen between VEGF grade and chemotherapy response. Conclusion: We can conclude from this study that VEGF is significantly overexpressed in cancer mucosa as compared to normal mucosa and overexpression of VEGF was found to be associated with chemoresistance and thus may serve as a negative predictive marker.