PURPOSE: Vascular Endothelial Growth Factor (VEGF) promotes angiogenesis in many different tumor types. VEGF levels may affect tumor growth, metastatic potential, and response to radiotherapy. This study assesses the prognostic value of VEGF protein levels in a cohort of patients with oral and oropharyngeal squamous cell carcinomas. The relationships between clinical outcome and the covariables of tumor-node-metastasis stage, disease stage (I to IV), grade, margin status, race, sex, and age were also determined. PATIENTS AND METHODS: Chart review identified 77 patients with oral or oropharyngeal squamous cell carcinoma treated with gross total surgical resection and postoperative radiation between 1981 and 1992. Sufficient follow-up data and tumor tissue were available in 56 patients (73%). VEGF protein levels were determined using immunohistochemistry. The association between VEGF status, covariables, and outcome was assessed in a bivariate and multivariate model using two-sided statistical tests. RESULTS: Twenty-three tumors (41%) were positive for VEGF expression. VEGF-positive tumors were more likely to recur locally (relative risk [RR] = 3.08; 95% confidence interval [CI], 1.03 to 9.24) and distantly (RR = 4.62; 95% CI, 1.41 to 15.10). In bivariate analysis, VEGF positivity was the most significant predictor of poor disease-free survival (RR = 2.66; 95% CI, 1.27 to 5.56) and overall survival (RR = 3.21; 95% CI, 1.63 to 6.32). In multivariate analysis, VEGF positivity was the most significant predictor of poor disease-free survival (RR = 2.75; 95% CI, 1.30 to 5.79) and overall survival (RR = 3.53; 95% CI, 1.75 to 7.13). CONCLUSION: In this cohort, VEGF positivity was the most significant predictor of poor prognosis. VEGF status may prove to be an important prognostic factor in head and neck cancer.