The aim of this study was to assess the efficacy and safety of two protocols for retreatment of a cohort of Egyptian patients with chronic hepatitis C (CHC) who relapsed after NS5A inhibitor-based therapy. We conducted a prospective cohort study to assess the safety and efficacy of 12 weeks’ retreatment with either combination of sofosbuvir/daclatasvir/simeprevir plus ribavirin (SOF/DCV/SMV/RBV, n = 45) or sofosbuvir/ ombitasvir/paritaprevir/ritonavir plus ribavirin (SOF/OBV/PTV/r/RBV, n = 163) in patients who had previously failed NS5A inhibitors-based regimens. The primary end point was SVR 12 weeks after the end of treatment (SVR12). Safety follow-up data were recorded for 60 weeks after the end of treatment. Two hundred eight patients were included in the study. Of them, 53.4% of patients were females and 40.4% had liver cirrhosis. The most common prior drug combinations were sofosbuvir/daclatasvir (n = 94) and sofosbuvir/daclatasvir plus ribavirin (n = 109). The overall SVR12 rates were 98.1%. In SOF/DCV/SMV/RBV group, 95.6% achieved SVR12, while in SOF/OBV/PTV/r /RBV group, the SVR12 rates were 98.8%. SVR12 was higher in cirrhotic patients (84/84) than noncirrhotic (120/124), P value = .0149. Regarding the safety outcomes, anaemia and fatigue were significantly higher in SOF/OBV/PTV/r/RBV group. Hepatocellular carcinoma (HCC) was reported in eight (3.8%) patients (four in each group). Of them, death was confirmed in four patients. Retreatment of Egyptian CHC relapsed patients with either sofosbuvir/daclatasvir/simeprevir plus ribavirin or sofosbuvir/ombitasvir/paritaprevir/ritonavir plus ribavirin is highly effective and well-tolerated for both noncirrhotic and compensated cirrhotic patients. Incidental de novo HCC and hepatic decompensation are comparable in the two groups.