We aimed to evaluate the therapeutic effect and complications of combined intravitreal melphalan and intravenous/intra-arterial chemotherapy as a primary approach for retinoblastoma with vitreous seeds. In this retrospective case series, eight eyes from eight retinoblastoma patients with vitreous seeds were included. All eyes received 20–30 μg of intravitreal melphalan accompanied by intravenous and intra-arterial chemotherapy. Triple freeze-thaw cryotherapy was performed when withdrawing the needle from the eye to prevent tumor dissemination. Tumors and vitreous seeds regressed in all eyes. The mean number of intravitreal melphalan injections was 3.25 (median 3.50, range 2–4). Globe salvage was attained in seven of eight eyes (87.5 %). Enucleation was performed in one case, in which the pathologic section showed no residual tumor and tumor-free resection margins. Serous retinal detachment was observed in four eyes (50 %), and vitreous hemorrhage developed in two (25 %). Retinal pigment epithelium atrophy or mottling was found in three eyes (37.5 %). There were no cases of extraocular tumor extension or remote metastasis. Combined intravitreal melphalan and intravenous/intra-arterial chemotherapy was effective for tumor and vitreous seeding control, but vision-threatening complications such as vitreous hemorrhage or serous retinal detachment occurred in half the cases.