Background: Hepatitis C Virus infects about 185 million people equating 2.8% of worldwide population and about 500,000 people die annually from hepatitis C related liver diseases. The most common clinical presentation of the disease is the chronic hepatitis and its complications such as: Compensated cirrhosis, portal hypertension, decompensated cirrhosis and Hepatocellular Carcinoma (HCC). Therapeutic management of chronic HCV patients traditionally depended on combination of peg-interferon (IFN) with ribavirin but this regimen showed many serious side effects beside its nonsatisfactory efficacy. In 2013, a second generation of Direct Acting Antiviral Agents (DAAs) gave a promising efficacy and safety. Although many IFN free regimens were approved, further evaluations are needed for these regimens. Aim: To compare sofosbuvir in combination with Daclatasvir, Ledipasvir and Simeprevir in patients with chronic hepatitis C infection according to safety, efficacy, relapse and patient outcomes. Patients and Methods: This is a prospective study conducted on 150 patients of chronic HCV who were admitted to the Viral Hepatitis Center in Al-Ahrar Educational Hospital in Zagazig {National Committee for the Control of Viral Hepatitis (NCCVH) during the first 9 months of 2017 and were selected according to the inclusion and exclusion criteria set by the (NCCVH). 58% of overall participants had cirrhosis and 2.7% were treatment-experienced. Patients were assigned into three groups: 50 patients received Sofosbuvir + Daclatasvir ± Ribavirin (SOF/DCV ± RBV) therapy, 50 patients received Sofosbuvir + Ledipasvir ± Ribavirin (SOF/LDV ± RBV) therapy and 50 patients received Sofosbuvir + Simeprevir ± Ribavirin (SOF/SIM±RBV) therapy. Three regimens were given for 12 weeks. Primary end point was the rate of achieving SVR12 by HCV RNA PCR, while secondary end point was the occurrence of virologic relapse.