Objective: To investigate the efficacy and safety of daclatavir combined with sofosbuvir treatment in chronic hepatitis C (CHC) in the real world. Methods: A total of 56 CHC patients administrated with daclatavir (60 mg/d) combined with sofosbuvir (400 mg/d) in Huzhou Central Hospital from February to June in 2018 were enrolled. All patients were administrated with daclatavir combined with sofosbuvir for 12 weeks and followed up for 24 weeks. The virological response and the effect of antiviral therapy on hepatic fibrosis were analyzed. Non-structural protein 5A (NS5A) region mutation sequence was detected by Sanger method. Safety and the adverse events were observed. The t test, chi-square test and Mann-Whitney U test were used to analyze the data. Results: Hepatitis C virus (HCV) RNA of all patients treated with daclatavir and sofosbuvir was undectable after eight-week treatment. Sustained virological response at 12 weeks post-treatment (SVR12) was 98.1% (52/53). Gender, globulin, insulin, triglyceride and hemoglobin were correlated with virus clearance (χ²= 4.47, t=2.51, U=1.98, U=2.32 and t=2.03, respectively, all P<0.05). At 12 weeks of the end of the treatment, serum procollagen type Ⅲ, collagen type Ⅳ, liver stiffness measurement (LSM) value, aspartate aminotransferase-to-platelet ratio Index (APRI) score and fibrosis index based on the four factors (FIB-4) score were all improved (U=2.03, 2.15, 2.19, 2.12 and 2.26, respectively, all P<0.05). At 24 weeks of the end of treatment, these indexes showed clear improvement (U=2.09, 2.28, 2.24, 2.33 and 2.46, respectively, all P<0.05). Eight patients had Y93H or L31M resistance-related substitution mutations. Two out of eight patients with variants had negative coversion of HCV RNA and 44.4% (20/45) showed no variants after two weeks of treatment. There was no significant difference (χ² = 1.11, P > 0.05). During the treatment, patients developed dizziness, fatigue, nausea and vomiting, panic, insomnia, sleepiness and sexual function enhancement. Conclusion Daclatavir in combination with sophobuvir shows high virological response and good safety in the treatment of chronic hepatitis C, and liver fibrosis is improved after clearance of HCV.