Purpose To report five years of conservative treatment for advanced retinoblastoma with the direct intra‐arterial‐ophthalmic artery infusion of Melphalan alone or Melphalan and Topotecan. Methods 75 children (82 eyes) with advanced retinoblastoma (Stage D‐E/VA –VB) were entered in phase two of one center open study‐approved protocol of ophthalmic artery infusion (Italian intra‐arterial protocol, approved by the Ethic Commettee – University Hospital of Siena). Seven cases have been treated bilaterally. 40 eyes were first diagnosis (naïve) and 42 were relapses following chemotherapy and focal therapy and/or radiotherapy. Results Cannulation of the ophthalmic artery was performed by a femoral artery approach using microcatheters (magic 1.5) while the children were under general anesthesia and anticoagulated. Chemotherapy (Melphalan alone or Melphalan and Topotecan) was infused into the artery over a 30‐minute period (dose of 3‐7 mg of Melphalan and 0.3‐0.4 mg of Topotecan, according to the age and size of the globe). Local and systemic toxicity have been evaluated and documented. Conclusion 75 children (82 eyes) with advanced retinoblastoma were eligible for the intra‐arterial Italian Protocol. The 65.8% of all treated eyes is in complete remission. Superselective chemotherapy delivered through the ophthalmic artery can avoid enucleation, primary radiation or abuse of systemic chemotherapy.