Abstract Background The emergence of direct antiviral agents (DAAs), and the campaign done by the National Committee for Control of Viral Hepatitis (NCCVH) have reduced chronic hepatitis C (CHC) prevalence in Egypt. Objectives evaluate the efficacy and safety of used DAAs in affiliated centers. Methods an observational prospective and retrospective study including140 eligible patients from October 2017 till December 2019 and who were either starting treatment or during follow- up for 1 year after the end of therapy (EOT). Patients were divided according to the treatment regimen into Group I (SOF/DAC for 12 weeks), Group II (SOF/DAC/RBV for 12 weeks), Group III (SOF/SIM for 12 weeks), Group IV (SOF/DAC for 24 weeks) and Group V (SOF/DAC/RBV for 24 weeks). Results DAAs were effective in all groups. Adverse effects occurred in 54 patients (38.6%). The most common complications that occurred were ascites (n = 18) followed by jaundice (n = 17) and hepatocellular carcinoma (HCC) (n = 14). Almost all patients (97.1%) in group IV complained of adverse effects compared to other groups with a statistically significant difference (p < 0.001). Hematemesis occurred in one patient among the whole groups and this patient had been in group IV. There was also a significantly higher proportion of ascites (38.2%) in group IV compared to other groups (p < 0.01), however no significant differences between groups regarding HCC and renal impairment (RI) (p-value= 0.316 and 0.758 respectively) were found. 49 naïve patients suffered from side effects, 31 patients were in group IV, followed by group I (n = 7) then group II (n = 6). 5 experienced patients reported side effects. RI was the most reported side effect (12.5%) among interferon (IFN) experienced and SOF/DAC experienced patients and who were treated among group IV and group V. Hepatic encephalopathy was equally reported (12.5%) in IFN experienced and SOF/RBV experienced patients among group IV or group V. Ascites (6.3%) and jaundice (6.3%) also were reported among group IV. No experienced patient has complained of hematemesis or HCC. Conclusion SOF/RBV treatment for 24 weeks had many side effects and should be used with caution.