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The purpose of this study was to report significant alterations in orbital vasculature after combined systemic chemoreduction with consolidating external beam radiotherapy treatment in a case of advanced retinoblastoma and to discuss implications for intraarterial melphalan rescue chemotherapy.We studied the case of a 22-month-old child who had been treated recently with intraarterial melphalan perfusion after multimodal therapy for advanced intraocular retinoblastoma.Orbital angiography of both eyes, performed before the intraarterial melphalan injection, documented an atypical attenuated orbital vasculature. The right ophthalmic artery angiogram showed loss of a normal dominant central retinal artery. Instead, multiple dysplastic angiogenic vessels from the ophthalmic artery were found to supply the retina. A single long ciliary artery was noted with collateral vessels supplying the anterior globe. The left ophthalmic artery angiogram showed a stenotic artery with minimal anterograde flow.Orbital vasculature may be impacted by combined systemic chemotherapy and external beam radiation therapy. These changes need to be considered in the use of intraarterial melphalan for the treatment of patients with advanced retinoblastoma.