Purpose: To investigate retinal changes in β-thalassemia major patients and identify their association with systemic risk factors. Methods: In this prospective study, 120 β-thalassemia major patients received complete ophthalmic examinations (best-corrected visual acuity, contrast sensitivity, color vision, and indirect ophthalmoscopy) and retinal imaging using color fundus photography and fundus autofluorescence imaging. Patients were grouped according to the presence of thalassemia-related retinal changes. The association between systemic risk factors (age, type and duration of iron chelator use, history of splenectomy, hemoglobin level, and ferritin level) and thalassemia-related retinal changes was investigated using logistic regression analysis. Results: Thalassemia-related retinal changes were identified in 36.7% of patients. Several distinct retinal changes were observed, including retinal refractile bodies in 10% of patients and retinal hemorrhage in 5.8% of patients. Fundus autofluorescence imaging showed abnormal patterns in 36.3% of patients with thalassemia-related retinal changes and 18.4% of patients without thalassemia-related retinal changes. Age (odds ratio [OR] = 1.10, 95% confidence interval [CI] 1.03–1.18) and ferritin level (OR 1.16, 95% CI 1.01–1.33) were associated with thalassemia-related retinal changes. Conclusion: Novel retinal changes were observed in β-thalassemia major patients. This study identified older age and higher ferritin level as risk factors for thalassemia-related retinal changes. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.