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Objective: In some cases of chemoresistant or recurrent intraocular retinoblastoma (Rb) external beam radiotherapy (RT) is the only way to save the eye. Conventional RT leads to severe complications including bone deformities, secondary malignant tumors, and currently has very limited use. There is no information about Gamma-knife single fraction radiosurgery (GK-RS) in the management of Rb. The purpose of our study is to present the first experience of successful Rb treatment with GK-RS as an alternative to enucleation. Methods: Five patients (aged 26, 31, 35, 43, and 114 months) with Rb Group B (one) and Group D (4 patients) were treated with GK-RS as the only capacity to save the eye. Previously all patients received different kinds of chemotherapy including systemic (vincristine, etoposide, and carboplatin), intra-arterial (Melphalan or/and Topotecan) and intravitreal (Melphalan alone or in combination with Topotecan). All patients had chemoresistant Rb with no capability to use any local treatment (brachytherapy, cryo, or laser). In cases of massive vitreous Rb (three patients) irradiation dose of 20-22 Gy at 50% isodose curve was prescribed along the inner MRI/CT contour of the eye globe and lens. The juxtapapillar tumors in two patients were treated with 24 Gy at 49% and 35 Gy at 90% isodose curve. Doses for critical structures (the fovea, optic nerve, lens, ciliary body, orbital bones) have been also taken into consideration, collected, and will be presented. Results: Complete tumor regression was achieved in three patients: one patient with juxtapapillar tumor and two patients with vitreous Rb. In two patients with vitreous and juxtapapillar Rb more than 50% regression was seen. Vitreous hemorrhage occurred within 7 months after treatment in one patient with vitreous Rb and was successfully managed with pars plana vitrectomy with melphalan irrigation. Optic neuropathy was detected within 6 months in one patient and regressed after subtenon steroid therapy. Mild retinopathy was seen and successfully treated in one eye. One patient developed eccentric opacities of posterior lens capsule. No signs of iridocyclitis, keratopathy, and damage of extraocular muscles, orbital walls, or brain were seen. Follow-up was from 3 to 25 months. All patients are still under control. Conclusions: The first to our knowledge world experience of GKRS for retinoblastoma showed that it may be a reasonable and successful treatment as an alternative approach to enucleation in selective cases. Procedure was well tolerated and had no severe complications. GK-RS should be considered in retinoblastoma management.