Background: Introduction: HCV infection causes significant impairment of health-related quality of life (HRQoL) and other patient-reported outcomes. Interferon-based treatment was strongly associated with a decreased HRQoL. Clinical trials showed that an interferon-free treatment also leads to a mild impairment of HRQoL during treatment that improves after end of treatment. Our aim was to assess the impact of Direct Acting Antiviral (DAA) treatment on HRQoL in a prospectively followed real-life cohort in the context of community-led program. Methods: HRQoL was assessed in 601 HCV-infected patients using the Short-Form 36 before the start of DAA treatment and was repeated after about 12 weeks of end of treatment when SVR was assessed. The patients were classified into two groups according to treatment regimen: Group I patients received 400 mg of sofosbuvir daily with weight-based ribavirin for 24 weeks, while Group II patients received daily oral sofosbuvir 400 mg and daclatasvir 60 mg for 12 weeks. Results: HRQoL domains (with the exception of role physical domain) showed improvement, regardless whether ribavirin was part of the treatment regimen or not. Both the physical and the mental component summary score increased significantly in each group, with no significant difference between the two treatment arms. Conclusion: The current real-world study confirms results from clinical trials that the majority of patients report an increased HRQoL after finishing HCV treatment.