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To determine the efficacy of primary intravenous chemotherapy (IVC) plus secondary intraarterial chemotherapy (IAC) for patients with advanced retinoblastoma.Retrospective, nonrandomized interventional case series of 14 patients with retinoblastoma managed with primary systemic IVC (vincristine, etoposide, and carboplatin for 6 cycles) followed by secondary IAC (melphalan for 1–6 cycles).Fourteen patients with advanced retinoblastoma classified by the International Classification of Retinoblastoma as Group D (n = 6, 43%) or Group E (n = 8, 57%) were treated with IVC as primary treatment and subsequent secondary IAC as rescue or consolidation therapy. The IAC was given for recurrent retinoblastoma and/or subretinal/vitreous seeds in 13 eyes (93%) and for persistent viable retinoblastoma in 1 eye (7%). Enucleation was the alternative option. The mean interval between IVC completion and IAC start was 40 weeks (median, 11 weeks; range, 2–170 weeks) and the mean number of IAC cycles was 3 (median, 3; range, 1–6). After primary IVC plus secondary IAC, globe salvage was achieved in 8 patients (57%) at mean 2-year follow-up. There was no evidence of retinoblastoma metastasis or death and no sign of second cancer or life-threatening complication.For advanced retinoblastoma (Groups D and E) in which enucleation is the alternative option, primary systemic IVC followed by secondary focal IAC provides globe salvage in 57% of the eyes and with no metastatic event.