Introduction: Sickle cell disease (SCD) affects multiple organs, including the eye. Optical coherence tomography (OCT) is a quick, noncontact test that provides high-resolution images of distinctive retinal layers. OCT has revolutionized ophthalmology examination and offers valuable new information on retinal damage in SCD. Our earlier studies show that OCT has a higher detection rate for retinal changes in SCD, offering earlier diagnosis than fundoscopy alone. Additionally, abnormal retinal OCT correlates with cerebrovascular disease (CVD) strongly suggesting that retinal OCT may aid in detecting and monitoring SCD related brain injury. One of the characteristics of SCD is the marked variability in patients' clinical manifestations. SCD genotype impacts the presentation of sickle cell retinopathy (SCR). Though OCT has revealed a higher frequency of SCR and more extensive retinal changes associated with the more severe SCD genotypes SS and Sβ0 as compared to SC, significant heterogeneity remains even among patients with the same genotype. Early identification of factors predictive of organ damage, such as SCR and CVD, will allow initiation of individualized disease-modifying treatment before organ systems suffer repeated hypoxic-ischemic events, thus improving long-term outcomes. Degree of hemolysis and fetal hemoglobin (FHb) are among the most important factors affecting SCD severity. There have been limited studies on their effect on ocular health in children with SCD. Methods: The Delaware Comprehensive Sickle Cell Research Center performed a prospective longitudinal cohort study in which all participants underwent complete ophthalmologic examination and OCT imaging. Posterior pole volume scans centered at approximately 3 mm temporal to the foveal were obtained. Areas of retinal thinning were identified using the thickness map. Medical history, brain imaging and laboratory data were collected. All available FHb values were recorded to examine the changing trend with age. Retinal findings were correlated with brain imaging and clinical data. Analysis was performed using IBM SPSS Statistics 27 (IBM, Armonk, NY). The Chi-square test was used for categorical data, and the nonparametric test for continuous variable analysis. The relationship between FHb, age at FHb testing and OCT was examined using multiple regression analysis. Results: From July 2015 to April 2023, 181 (88 males) patients aged 5.35 - 20.39 (12.72 ± 4.29) years with SCD (108 SS, 56 SC, 10 Sβ+ thalassemia, 5 Sβ0 thalassemia and 2 other) enrolled in the study. Visual acuity ranged 20/20 - 20/40. On funduscopic exams, 23 of 181 (12.71%) showed signs of SCR, whereas 107 (59.12%) had retinal injuries on OCT. Seventy-six patients with SS/Sβ0 genotype had brain MRI, and 28 had abnormal findings (Table). Twenty-four of the 28 patients (85.71%) also had abnormal OCT (p = 0.021). Children with SC and SS/Sβ0 disease with normal retinal OCT had FHb values significantly higher than those with abnormal OCT (Z =-2.61 and -4.16, p = 0.009 and 0.000). Children with SS/Sβ0 disease, abnormal OCT had more elevated reticulocyte counts than those with normal OCT (Z = -2.848, p = 0.004). SS genotype were evaluated for FHb values. As expected, FHb levels decline with age, and the rate of descent diminishes (i.e., more rapid fall at an early age). Interestingly, the decrease in FHb is significantly more profound before age 15 for patients with abnormal OCT than those with normal OCT (Figure). The effect of hydroxyurea (HU) in preventing SCR is inconclusive. Children with normal OCT had similar FHb levels without and with HU. However, HU raises FHb levels among those with abnormal OCT. Conclusions: 1) Retinal and brain injury correlates in SS/Sβ0, and OCT may help to select patients for MRI. 2) Abnormal OCT is associated with increased reticulocyte count, indicating heightened hemolysis. While AST and indirect bilirubin levels are not significantly different between normal and abnormal OCT groups in the current dataset, we will repeat the analysis of these hemolytic markers with a larger sample. 3) Early serial measurement of FHb levels throughout childhood can identify patients at high risk for subsequent severe complications such as SCR and CVD who might benefit from early disease modifying treatments. These important findings and the impact of hydroxyurea require further study in a larger patient population undergoing serial exams.