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BACKGROUND AND OBJECTIVES: Data regarding the safety and efficacy of antiviral therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV) in patients with sickle-cell disease (SCD) and hepatitis C virus (HCV) infection are scanty. In this study, our aim was to evaluate the safety and efficacy of antiviral therapy with PEG-IFN and low-dose RBV in patients with SCD and chronic HCV infection receiving hydroxyurea in Saudi Arabia. DESIGN AND SETTINGS: This was a prospective interventional study conducted between January 2009 and September 2012 at the outpatient departments of Haematology and Hepatology/Gastroenterology of a tertiary care hospital in Saudi Arabia. PATIENTS AND METHODS: We studied 8 treatment-naive patients (5 males, 63%) with chronic hepatitis C and SCD receiving hydroxyurea who were treated with PEG-IFN alpha-2a (180 μg weekly) and low-dose RBV (200 mg daily). Early virological response (EVR) and sustained virological response (SVR) rates were assessed in all patients. RESULTS: All patients were infected with HCV genotype 1 (n=6.8%) or 4 (n=22%). EVR was obtained in 3 patients (38%) and SVR in 6 patients (7%). During the study, there was no increase in the number of blood units transfused and emergency visits due to painful crises. CONCLUSION: in Saudi Arabian patients with SCD and chronic HCV infection on hydroxyurea, PEG-IFN and low-dose RBV treatment proved to be efficacious and safe.