We prospectively evaluated vascular endothelial growth factor (VEGF) expression by immunohistochemistry in 22 consecutive IRSS stage III retinoblastoma patients who underwent enucleation after neoadjuvant chemotherapy (NACT). Positive VEGF expression was observed in 6/22 (27.3%) patients. VEGF expression was associated with local progression on MRI prior to enucleation (P = 0.004), pathological scleral (P = 0.023), and extra-scleral tumor extension (P = 0.009). EFS for VEGF positive and negative patients was 0% and 56.25%, respectively (P = 0.0002). OS for VEGF positive patients was 33.33% and 54.69% for VEGF negative patients (P = 0.207). Thus, VEGF in residual tumor cells post-NACT may represent poor response to NACT, potential for local invasion, and inferior outcome.