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Alfosbuvir is a novel potent HCV NS5B polymerase inhibitor in development for the treatment of chronic HCV infection. Our previous studies indicated that alfosbuvir monotherapy was well‐tolerated and druggable in healthy subjects and HCV‐infected patients. Here, we evaluate the efficacy and safety of alfosbuvir in combination with daclatasvir in Chinese patients with HCV genotype 1, 2, 3 or 6. In this open‐label study, patients with chronic HCV infection were randomly assigned with a 1:1:1 ratio to receive 12 weeks of daclatasvir 60 mg plus alfosbuvir at a dose of 400, 600 or 800 mg (Cohort A, B or C) daily. Randomization was stratified by HCV genotype and the presence or absence of cirrhosis at screening. The primary endpoint was a sustained virologic response 12 weeks after the end of treatment (SVR12). A total of 124 patients were enrolled in the study, all of whom were available for post‐treatment week 12 assessments. SVR12 was achieved in 92.7% (38/41), 95.2% (40/42) and 100% (41/41) of patients in Cohort A, B and C respectively. The most common adverse events were hepatic steatosis, upper respiratory tract infection, hypercholesterolaemia, hypertriglyceridaemia, blood bilirubin increased, and total bile acids increased. There were no discontinuations due to adverse events, and no treatment‐related serious adverse events were reported. Once‐daily oral administration of alfosbuvir plus daclatasvir were highly effective and safe in Chinese patients infected with HCV genotype 1, 2, 3 or 6, suggesting this regimen could be a promising drug candidate for HCV treatment irrespective of genotype. (ClinicalTrials.gov number, NCT04070235). [ABSTRACT FROM AUTHOR]