A case series of three patients by Francis et al. has investigated the response and toxicity of intravitreal melphalan treatment for non-vitreous retinoblastoma that was refractory to multiple-course ophthalmic artery chemosurgery (OAC). Patients Three eyes received a median of 7 weekly intravitreal melphalan injections (30μg/0.07cc). The toxicity of treatment was measured by electroretinogram (ERG) and the response to treatment was clinically evaluated. All eyes remained tumor-free at a median of 14 months follow-up. One eye was enucleated due to a vitreous hemorrhage that obscured fundus details. One eye had extinguished ERG recordings prior to injections and two eyes had a decrease in ERG responses over the intravitreal treatment course. The eye with subretinal seeding demonstrated marked retinopathy by ophthalmoscopy and fluorescein angiography and one eye was enucleated due to the development of a vitreous hemorrhage. This small case series highlights that non-vitreous disease that is refractory or persistent despite prior OAC can regress with intravitreal melphalan. However, this treatment may result in retinal toxicity.