Abstract Background: Treatment of Hepatitis C Virus (HCV) infection had significantly changed during the last few years. The combination of Sofosbuvir and Ledipasvir (SOF/LDV) has been shown to treat high proportions of patients with HCV. Aim of Study: The aim of the work was to assess the efficacy and risk factors for failure of SOF/LDV in Egyptian patients with HCV infection. Patients and Methods: In this prospective study, 138 patients who were HCV antibody positive and HCV RNA positive by Polymerase Chain Reaction (PCR), aged between 18 and 75 years, were enrolled. The patients assessed demo-graphically, and by laboratory and ultrasound. The patients received daily Sofosbuvir 400mg plus Ledipasvir 90mg for 12 weeks, the primary end point was a sustained virological response at 12 weeks (SVR12) after the end of treatment, determined by quantitative PCR for HCV RNA. The patients were classified into two groups according to SVR12: Respond-ers included 133 patients who had undetectable level of HCV RNA and non-responders included 5 patients who had detect-able level of HCV RNA. Results: The overall SVR12 was 96.4%. The response of cirrhotic vs. non-cirrhotic patients was (80% vs. 98.4) with statistically significant p-value (p<0.05) with specificity 90% and sensitivity 60% (odds ratio=15.125, 95% confidence interval 2.29-99.6, p<0.05), and the response of naïve vs. experienced patients was (97.6% vs. 83.3%) with statistically significant p-value (p<0.05) with specificity 92.5% and sensitivity 40% (odds ratio=8.2, 95% confidence interval 1.22-54.9, p<0.05). Conclusion: Sofosbuvir/Ledipasvir combination for 12 weeks was very effective for chronic HCV treatment, cirrhosis and treatment-experienced patients were associated with decreased likelihood of SVR.