Purpose: To report our experience in the management of cataracts presumably due to intravitreal chemotherapy administration in eyes with vitreous disease associated with retinoblastoma. Methods: This retrospective study consisted of a cohort of five eyes of five retinoblastoma patients who developed cataracts secondary to intravitreal chemotherapy administration and who then underwent cataract surgery. All patients underwent lensectomy and anterior vitrectomy with/without intraocular lens implantation via clear corneal approach. All cases were administered intraoperative intravitreal melphalan (35-40 mcg) and topotecan (10-20 mcg) at the end of cataract surgery as a preventive measure against retinoblastoma spread. Injections were repeated as needed in monthly follow-ups. Main outcome measures were enucleation rate and disease-free survival time. Results: The age at surgery ranged between 5 and 10 years. Follow-up time varied from 12 to 16 months. Treatment-free period before surgery ranged between 3 and 20 months. Time from last injection to cataract detection was: 2, 2, 10, 6, and 7 months; and time from last injection to cataract surgery was: 8, 3, 20, 7, and 15 months in cases 1-5, respectively. None of the eyes required enucleation. Tumor control was achieved in all patients at the end of follow-up. Conclusions: Injection of melphalan and topotecan into anterior parts of the vitreous may lead to cataract formation. This can be safely managed with lensectomy and anterior vitrectomy and the use of intravitreal administration of melphalan and topotecan at the conclusion of the surgery as a precautionary measure against the potential risk of extraocular spread.