Background: Egypt has the highest prevalence of hepatitis C virus (HCV) worldwide. Patients with sickle cell disease are more exposed to the risk of HCV infection. Genetic polymorphisms in IL28B gene have been associated with spontaneous HCV clearance. Aims: to determine the prevalence of both HCV infection and IL28B gene polymorphisms among pediatric patients with sickle cell disease and to explore the relation between IL28B gene polymorphisms and spontaneous HCV clearance. Methods: Seventy sickle cell disease patients were screened for HCV antibody. Detection of IL28B polymorphisms (rs 12979860 SNP and rs 12980275 SNP) were done using Taqman QRT-PCR and sequence specific primers PCR respectively. HCV RNA was measured in sera of HCV positive patients using quantitative real time PCR. Results: Sixteen patients (23%) were positive for HCV antibodies. Nine patients (56.3%) had undetectable HCV RNA in serum (spontaneously cleared) and 7 patients (43.8%) were not cleared. Genotypes CC/CT/TT of rs12979860 were found in 30 (42.9%), 29 (41.4%) and 11 (15.7%) patients and rs12980275 AA/AG/GG were found in 8 (11.4%), 59 (84.3%) and 3 (4.3%) patients. There was no significant difference in the frequency of IL28B (rs 12979860) genotypes among HCV patients who cleared the virus and those with persistent viremia (p=0.388). Also, frequency of IL28B (rs12980275) genotypes did not differ between the two groups (p=0.438). Conclusion: Egyptian Sickle cell disease patients have high prevalence of HCV. IL28B gene polymorphisms are not associated with spontaneous clearance of HCV in this cohort of Egyptian children with sickle cell disease.