Sickle cell retinopathy (SCR) is a complication of sickle cell disease (SCD). Proliferative SCR (PSCR) can lead to severe visual impairment due to vitreous hemorrhage or retinal detachment. Knowledge of risk factors for progression and complications of SCR is limited. The aim of this study is to describe the natural history of SCR and to identify risk factors for progressive SCR and development of PSCR. We retrospectively analyzed disease progression in 129 patients with SCD with a median follow-up period of 11 years (interquartile range, 8.5-12). Patients were divided in 2 groups. The genotypes hemoglobin SS (HbSS), HbSβ0-thalassemia, and HbSβ+-thalassemia were grouped together (n = 83; 64.3%), whereas patients with HbSC (n = 46; 35.7%) were grouped separately. Progression of SCR was observed in 28.7% (37 of 129) of patients. Older age (adjusted odds ratio [aOR], 1.073; 95% confidence interval [CI], 1.024-1.125; P = .003), HbSC genotype (aOR, 25.472; 95% CI, 3.788-171.285; P ≤ 0.001), and lower HbF (aOR, 0.786; 95% CI, 0.623-0.993; P = .043) were associated with PSCR at end of follow-up. Lack of any SCR at end of follow-up was associated with female sex (aOR, 2.555; 95% CI, 1.101-5.931; P = .029), HbSS/HbSβ0/HbSβ+ genotype (aOR, 3.733; 95% CI, 1.131-12.321; P = .031), and higher HbF levels (aOR, 1.119; 95% CI, 1.007-1.243; P = .037). Differentiated strategies for screening and follow-up of SCR could be considered for patients at low or high risk.