Background: Hepatitis C virus (HCV) is a major health problem. Current treatment by direct-acting antivirals achieved high sustained virological response (SVR). However, drug intolerance or relapse may occur. We aimed to demonstrate the safety of sofosbuvir (SOF) plus daclatasvir (DCV) regimen in Egyptian patients with hepatitis C infection and the assessment of resistance associated variants (RAVs) in non-responders. Methods: In this prospective study, 850 HCV patients eligible to SOF + DCV ± ribavirin (RBV) were recruited. They were divided into two groups; patients with chronic hepatitis C (CHC) and patients with liver cirrhosis. Baseline data included clinical history, examination, routine laboratory tests and HCV viral load. Safety evaluation was assessed during treatment up to 12 weeks after the end of treatment. RAVs assessment was considered at baseline and in cases of relapse. Results: CHC group included 548 patients while 302 had liver cirrhosis. The most frequent adverse events were headache 20%, fatigue 14%, myalgia 5.2%. Diarrhea occurred in 4.6% with significantly higher frequency among liver cirrhosis group; 7.3% vs. 3.1% (P= 0.04). No patients had to stop treatment because of adverse events. SVR was achieved in 91.2% while 75 (8.8%) had relapse. At baseline, RAVs were found in 10%. After therapy, RAVs (E237D) were detected in 1 non-responder. Conclusion: Treatment with SOF/DCV was effective and well tolerated in patients with HCV. RAVs testing is not routinely recommended before treatment as resistant variants could occur naturally in HCV.