Objective: To assess the efficacy and safety profile of antaitasvir phosphate combined with yiqibuvir in the treatment of chronic hepatitis C (CHC) of various genotypes, without cirrhosis or with compensated cirrhosis. Methods: 394 cases with CHC from 22 centers were collected from October 2021 to April 2023. They were randomly assigned to receive either the experimental drugs (antaitasvir phosphate 100 mg+yiqibuvir 600 mg) or placebo treatment in a 3∶1 ratio. The patients were administered drugs once a day for 12 consecutive weeks, and then followed up for 24 weeks after treatment cessation. All subjects were unblinded at the four-week follow-up following drug discontinuation, with the experimental drug group continuing to complete subsequent post-discontinuation follow-up. The placebo group was switched to receive the experimental drugs for a repeated 12-week treatment period and followed up for another 24 weeks after discontinuation of the drug (placebo delayed treatment phase).The sustained virologic response rate (SVR12) was observed for subjects in the double-blind phase and the placebo delayed-treatment phase at 12 weeks after treatment cessation.Virological resistance analysis was performed on subjects who failed treatment. The primary efficacy endpoint was SVR12. The number and percentage of subjects who achieved "HCV RNA<quantitative lower limit" with the experimental drug (antaitasvir phosphate capsule combined with yiqibuvir tablet) were calculated. The safety profile of the drug was evaluated by the incidence and severity degree of adverse events. All efficacy endpoints and safety profile data were summarized using descriptive statistical methods. Results: The results of the full analysis set (FAS) showed that the overall SVR12 rate in the experimental drug group during the double-blind phase was 94.1% (270/287), with SVR12 rates for genotypes 1, 2, 3, and 6 were 98.6% (138/140), 98.4% (60/61), 75.0% (33/44), and 92.9% (39/42), respectively. The SVR12 rate for subjects with compensated cirrhosis was 90.9% (30/33) and those without cirrhosis was 94.5% (240/254). A total of 96 subjects in the placebo group entered the placebo delayed treatment cohort, with an overall SVR12 rate of 95.8% (92/96), with SVR12 rates for genotypes 1, 2, 3, and 6 were 100% (48/48), 100% (21/21), 84.6% (11/13), and 85.7% (12/14), respectively. The rate for subjects with compensated cirrhosis was 92.3% (12/13), and those without cirrhosis was 96.4% (80/83). The results of virology resistance analysis suggested that most virological failures in this study was associated with newly introduced mutation sites or increased mutation proportions, with baseline amino acid mutations had no overall impact on the SVR12 treatment outcomes. The adverse events (TEAEs) related to the experimental drug during this study were mostly grade 1 or grade 2, primarily including hyperuricemia, hypercholesterolemia, and hypertriglyceridemia, with overall good safety and well-tolerability. A total of one case (0.3%) in the experimental drug group was suspended due to TEAEs (fatigue, dizziness, and myalgia), but no TEAEs occurred that led to permanent discontinuation of the drug, termination of treatment, early withdrawal, or death. Conclusions: The combination of antaitasvir phosphate 100 mg combined with yiqibuvir 600 mg demonstrates significant efficacy and a good safety profile in patients with CHC with genotypes 1, 2, 3, and 6, without cirrhosis or with compensated cirrhosis, who have received interferon-based treatment or have received initial treatment.