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To report a case of a boy with bilateral germinal retinoblastoma and Down syndrome who was successfully treated despite a predilection toward chemotoxicity associated with Down syndrome.A 3-month-old boy presenting with germinal retinoblastoma and Down syndrome was treated with diode laser and systemic carboplatin and low-dose vincristine, with gradual dose escalation. Etoposide and cyclosporine were later added for a greater tumor response. After cyclosporine was added, the patient was hospitalized due to vincristine toxicity. The vincristine dose was further lowered, and periocular carboplatin injections were given to establish control of intraocular disease.The tumors regressed after 11 sessions of laser and chemotherapy. Because of residual vitreous seeding in the right eye, a series of two periocular carboplatin injections were given. Six more laser sessions were applied to the tumors. There is no evidence of active retinoblastoma after 11 months of follow-up.Because of increased chemosensitivity in patients with Down syndrome, it is important to reduce systemic drug dosages and consider augmenting local therapy in retinoblastoma cases.