The presence of active vitreous seeding following state-of-the-art conservative treatment of intraocular retinoblastoma leads in the vast majority of cases to either external beam irradiation (EBR) and/or enucleation. Intravitreal chemotherapy (IVC) is theoretically the best route for delivering the highest vitreous concentration of a chemotherapeutic drug, over intravenous, periocular and ophthalmic artery chemotherapy. This makes IVC the best candidate for treatment of diffuse vitreous disease in eyes with retinoblastoma, but it has remained highly controversial, as considered an invasive procedure associated with the risk of tumor exteriorization. We retrospectively reviewed all consecutive patients with vitreous disease found eligible and then treated by intravitreal injections of melphalan. IVC was performed every 7 to 10 days up to 8 injections of Melphalan (20-30 mg) per event, using a novel injection technique characterized by the prevention of vitreous reflux and sterilization of the needle track. The results appear promising in terms of safety (with no evidence of exteriorization), and efficacy with unprecedented salvage rate over 85%. Control of vitreous seeding was achieved without EBR in all cases.