Background: Chronic hepatitis C virus (HCV) is considered as a major cause of liver diseases. The standard treatment of HCV infection is a combination of direct-acting antiviral agents (DAAs). Relapse is defined where HCV RNA remained undetectable at the end of therapy but rebounded to pretreatment levels once DAA therapy was discontinued. Aim of the study: This study was performed to compare efficacy and safety of two quadruple DAAs regimens (Sofosbuvir/Daclatasvir/Simeprevir and Ribavirin Vs. Sofosbuvir/Ombitasvir/ Paritaprevir/ ritonavir - Ribavirin) in treatment of HCV relapsers. Patients and Methods: Retrospective cross-sectional study of 90 experienced patients previously treated with Sofosbuvir and Daclatasvir ± Ribavirin for 3 months and relapsed. The patients were divided into two groups, each group included 45 patients: Group I treated with (Sofosbuvir and Daclatasvir -simeprevir—Ribavirin) while Group II treated with (Sofosbuvir-Ombitasvir/Paritaprevir/ritonavir - Ribavirin). Results: The study showed an excellent response to both regimens of treatment. In group I; the sustained virologic response rates at 24th week were 44/45 (97.8%); 100% (29/29) in non-cirrhotic and 93.8% (15/16) in cirrhotic patients. while group II SVR 24 rates were 93.3% (44/45); 92.9% (26/28) of non-cirrhotic patients, and 94.1% (16/17) of cirrhotic patients. while group II SVR 24 93.3% (44/45) of overall patients, 92.9% (26/28) of non-cirrhotic patients, and 94.1% (16/17) of cirrhotic patients. Additionally, the most common adverse events reported were easy fatiguability, headache, nausea, generalized weakness, photosensitivity - in group I only. Conclusion: It could be concluded that the current combination regimen is well tolerated and achieved excellent SVR rates.