Background & Aim: Retinoblastoma is the most frequent intra-ocular tumor in childhood. The tumor has both endophytic and exophytic patterns of growth. After enucleation, the pathologist is called on to evaluate risk of further growth for prophylactic therapy. Invasion of the choroid or optic nerve are risk factors for developing metastases, but occasionally, metastatic or locally invasive tumors occur in the absence of these risk factors. In this study, correlation of vascular density using CD31 with vascular endothelial growth factor(VEGF) and also both of these markers with local invasive growth of retinoblastoma were assessed. Patients and Methods: The study was analytical cross-sectional and performed on sections of paraffin-embedded blocks of 37 enucleated eyes due to retinoblastoma, at Ophthalmology Department of Hazrat Rasool Akram Hospital in years 2000-2006. Hematoxylin and Eosin stained slides were reviwed for evaluation of local invasive growth of tumor. Vascular density by CD31 and VEGF was assessed by immunohistochemical staining(IHC), using an Strept avidin-Biotin Immunoperoxidase technique. For data analysis, T test, Chi 2 test, Phi test and ROC curve were used. Results: A CD31 number equal or greater than 62/10 HPF with 78.9% sensitivity and 66.7% specificity was considered as the most efficient cutt-off point and with VEGF as a qualitative test, were assumed as predictors for local invasion. Significant correlation was noted between VEGF and CD31. There was no correlation between CD31 and VEGF with uni or bilaterality, age, size and growth type. Conclusion: Assessment of vascular density with the use of CD31 and vascular endothelial growth factor(VEGF) can be useful method for prevention of local invasive growth of tumor and determining the need for prophylactic therapy in patients with advanced ocular retinoblastoma.