AIM: To evaluate the safety and efficacy of posterior sub-Tenon’s carboplatin injection compared to intravitreal melphalan injection in the management of retinoblastoma (RB) with secondary vitreous seeds. The outcome measures were vitreous seeds regression, need for other treatment modalities to achieve ocular salvage and treatment side effects. METHODS: A prospective interventional comparative nonrandomized study included RB eyes developed secondary vitreous seeds during the period of follow up. They subdivided into two groups: study group I where posterior sub-Tenon’s carboplatin (20 mg/2 mL) was injected and study group II where intravitreal melphalan (20 μg /0.1 mL) was injected. The injections repeated every 2-4wk. RESULTS: Thirty-three eyes were included in the study. Seventeen eyes (16 patients) in study group I and 16 eyes (16 patients) in study group II. Ten eyes (30.3%) were completely salvaged following local chemotherapies. Ocular salvage was 23.5% following posterior sub-Tenon’s carboplatin injection versus 37.5% following intravitreal melphalan raised to 47.1% and 75% with addition of external beam radiotherapy (EBR) with no statistically significant difference between the study groups (P=0.16). A statistically significant correlation was found between ocular salvage rate and type of vitreous seeds either dust, spheres and clouds (r=0.42, P=0.015) and eyes harbor new solid tumor growth (r=0.35, P=0.045). The mean and median follow up periods following local chemotherapy injections were 2.0y in the study group I and 2.37y in the study group II. Few complications were reported: periorbital edema in all eyes and ocular motility disturbances in 13 eyes (76.5%) following posterior sub-Tenon’s carboplatin injection. Vitreous hemorrhage developed in 2 eyes (12.5%) and localized retinopathy in 5 eyes (31.25%) following intravitreal melphalan. CONCLUSION: Local chemotherapy for treatment of RB with secondary vitreous seeds is safe and can salvage 30.3% of eyes without EBR. There is a superiority of intravitreal melphalan in ocular salvage however, no statistically significant difference between both groups.