PurposeTo describe the technique and evaluate the efficacy of intravitreal melphalan in advanced retinoblastoma with focal or diffuse vitreous seedingMethodsThis is a retrospective non‐comparative study. Our analysis was conducted at our referral center of retinoblastoma, Siena, Italy. The study included 19 eyes of 19 patients with naïve, persistent or recurrent vitreous seeding in advanced retinoblastoma. All eyes received intravitreal injection (20 μg) of melphalan under general anaesthesia .Outcome measures included vitreous seeding control and eyeball preservation, treatment complications and drug toxicityResultsWe used concomitant therapy, including systemic chemotherapy, intra‐arterial chemotherapy and peribulbar chemotherapy. All patients are alive without evidence of extraocular dissemination and global salvage was attained in 83% of cases. Complications included central vein thrombosisConclusionsThis study suggests that intravitreal melphalan injection for naïve, persistent and recurrent vitreous seeding can provide seeding control and avoid enucleation with minimal toxicity and complications.