To study the long-term safety and efficacy of intravitreal topotecan (IVT) against vitreous seeds in eyes with retinoblastoma and risk factors for their recurrence. Retrospective, non-comparative, interventional study. 91 eyes of 90 patients with retinoblastoma treated between January 2013 to April 2019. Patients with recurrent or refractory vitreous seeds following completion of intravenous or intra-arterial chemotherapy were treated with IVT (30μg/0.15ml) by the safety enhanced technique. The injection was repeated every 4 weeks till the regression of seeds. Patients with a minimum follow up of 12 months were included in the analysis. Primary outcome measures were vitreous seed regression, and eye salvage. Secondary outcomes were risk factors for vitreous seed recurrence following treatment with IVT, vision salvage and complications of IVT. The median age of the patients was 18 months, majority having group D (58, 64%) and group E (26, 29%) retinoblastoma. Vitreous seeds were refractory in 46 (51%) and recurrent in 45 (49%) eyes. A total of 317 IVT injections were given, median being 3. The median number of IVT injections required were 2.5 for dust, 3 for sphere and 5 for cloud morphology. Recurrence of vitreous seeds following IVT was seen in 17 eyes (19%) at a mean follow up of 7.9 months. At a mean follow up 34 months, vitreous seed regression was achieved in 88 (97%) eyes and eye salvage in 77 (85%) eyes. Older age (p=0.018) and recurrence of retinal tumor (15/17 eyes) (p<0.01) significantly increased the risk of vitreous seed recurrence. Cataract was the most common complication seen in 17 (9%) eyes. Intravitreal topotecan at a 3-4-weekly regimen is effective against both refractory and recurrent vitreous seeds. The vitreous seed morphology corresponds to the number of injections required for regression. Increasing age and recurrence of retinal tumor increase the risk of vitreous seed recurrence following treatment with IVT.