Approximately 71 million people worldwide are supposed to have chronic hepatitis C virus (CHCV). New direct-acting antiviral (DAA) medications have been used, which helped successfully in complete treatment of CHCV and achieved a sustained virological response (SVR). However, some patients may acquire HCV resistance to DAAs, which may result in treatments failure. The aim of the present study was to compare among the patients that were experiencing virologic relapse (VR) and SVR in relation to the patterns of NS5A and NS5B genes resistance associated substitutions (RASs) in the chronic HCV infected Egyptian patients, who received Sofosbuvir (SOF) and Daclatasvir (DCV) combination therapy. All patients that were infected by chronic HCV had completed treatment with SOF and DCV combination therapy and were followed up after the end of this treatment. A total of 10 out of 100 serum specimens were collected from the enrolled patients and analyzed, where two and eight specimens were representatives for VR and SVR, respectively. These samples had undergone reverse transcriptase-polymerase chain reaction amplification (RT-PCR) of NS5A and NS5B genes, partially sequenced by the Sanger method, and then analyzed phylogenetically to determine their genetic subtypes and RASs. Finally, SVR was gained in all but two patients who were experiencing VR that carried natural NS5A-RASs at positions L31M and Y93H. They were considered as significant for DCV resistance as well as natural NS5B-RASs (T282S), which represented the main polymorphism for SOF resistance. In this study, a number of mutational combinations in the analyzed NS5A and NS5B genes were identified, which may increase the risk of treatments failure in the patients administered regimens including multiple DAA, compared to the baseline sequences of those patients that were experiencing SVR.