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Background: Anti-vascular endothelial growth factor (Anti-VEGF) agents are a promising approach to increase the efficacy of treatment for treatment-resistant prostate cancer. Aims: To correlate vascular endothelial growth factor (VEGF) expression and outcome following radiation therapy in the treatment of clinically localized prostate cancer. Study Design: Retrospective observational study. Methods: Forty-one patients and clinically localized disease that were treated with radiation therapy were analyzed. For VEGF expression, immunoreactivity scores (IRS) were calculated using percent scores and intensity scores. Twenty-four patients were classified as having low (0 to 4 IRS) and 17 patients were classified as having high (5 to 8 IRS) VEGF expression. Results: The median age was 71 years, median follow-up was 5.4 years and median radiation therapy dose was 70 Gy. VEGF expression was calculated as low in 24 patients and high in 17 patients. Higher VEGF expression was observed in 6/26 patients with a low Gleason score versus 11/15 patients with a high Gleason score (p=0.02). Biochemical failure (BF) was observed in 2/24 patients with low VEGF expression versus 7/17 patients with high VEGF expression (p=0.01). In univariate analysis, having a higher Gleason score (p<0.01), being in the high risk group (p=0.03) and having higher VEGF expression (p=0.01) predicted BF after definitive radiation therapy. The biochemical failure-free survival rate at 5 years tended to be different (91% vs. 53%) when patients were grouped according to VEGF expression (p=0.06). Conclusion: In attempt to define patients with clinically localized disease that are not sensitive to standard treatment modalities, cellular and/or molecular biological markers may be required.