Background: Hepatitis C virus (HCV) remains a major health problem worldwide with over 170 million persons chronically infected and a burden of 300000 deaths. HCV Genotype 4 is the predominant Genotype in Egypt. During the past decade, a dual combination of pegylated interferon (PegIFN) and ribavirin (RBV) has represented the standard of care. In the era of directly acting antiviral drugs (DAAs), optimal treatment of HCV Genotype 4 remains, more than ever before, to be defined. Simeprevir (SMV) is a second generation NS3/4A protease inhibitor (PI), active against Genotypes 1, 2, 4, 5 and 6. Objectives: To determine the efficacy of Simeprevir-Sofosbuvir for treatment of chronic HCV infection among patients attending Sohag Cardiac and Digestive center (Ministry of Health), Upper Egypt. Patients and Methods: A prospective, hospital based, descriptive study, included 100 patients with chronic HCV infection eligible to receive Simeprevir-Sofosbuvir combination according to the Guidelines of the Ministry of Health. Results: Early virological response (EVR) was achieved in 99%. At the end of treatment, 94% were negative for HCV (ETVR). Finally, 89% of cases were still negative (sustained virological response) (virological response 12 weeks after end of treatment). The total occurrence of side effects among our study population was 13%, and all of them were mild. Conclusion: The combination of SOF and SMV is efficacious and well tolerated and represents a good therapeutic option in patients with chronic HCV in Upper Egypt.