Purpose: This study attempted to estimate the impact of eye-preserving therapies for the long-term prognosis of patients with advanced retinoblastoma with regard to overall survival and ocular salvage. Design: Retrospective cohort study covering all 31 provinces (38 retinoblastoma treating centers) of mainland China. Participants: One thousand six hundred seventy-eight patients diagnosed with group D or E retinoblastoma from January 2006 through May 2016. Methods: Chart review was performed. The patients were divided into primary enucleation and eye preserving groups, and they were followed up for survival status. The impact of initial treatment on survival was evaluated by Cox analyses. Main Outcome Measures: Overall survival and final eye preservation. Results: After a median follow-up of 43.9 months, 196 patients (12%) died, and the 5-year overall survival was 86%. In total, the eyeball preservation rate was 48%. In this cohort, 1172 patients (70%) had unilateral retinoblastoma, whereas 506 patients (30%) had bilateral disease. For patients with unilateral disease, 570 eyes (49%) underwent primary enucleation, and 602 patients (51%) received eye-preserving therapies initially. During the follow-up (median, 45.6 months), 59 patients (10%) from the primary enucleation group and 56 patients (9.3%) from the eye-preserving group died. Multivariate Cox analyses indicated no significant difference in overall survival between the 2 groups (hazard ratio [HR], 1.25; 95% confidence interval [CI], 0.85-1.84; P = 0.250). For patients with bilateral disease, 95 eyes (19%) underwent primary enucleation, and 411 patients (81%) received eye-preserving therapies initially. During the follow-up (median, 40.1 months), 12 patients (13%) from the primary enucleation group and 69 patients (17%) from the eye-preserving group died. For bilateral retinoblastoma with the worse eye classified as group E, patients undergoing primary enucleation exhibited better overall survival (HR, 2.35; 95% CI, 1.10-5.01; P = 0.027); however, this survival advantage was not evident until passing 22.6 months after initial diagnosis. Conclusions: Eye-preserving therapies have been used widely for advanced retinoblastoma in China. Patients with bilateral disease whose worse eye was classified as group E and who initially underwent eye preserving therapies exhibited a worse overall survival. The choice of primary treatment for advanced retinoblastoma should be weighed carefully. Ophthalmology 2022;129:209-219 (c) 2021 by the American Academy of Ophthalmology