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Background: Chronic hepatitis C virus (HCV) infection negatively impacts health-related quality of life (HRQL). We aimed to assess patient-reported outcomes (PROs) to evaluate the impact of treating chronic HCV with directly acting antivirals (DAAs) on HRQL. Methods: PROs were assessed prospectively using the PROQOL-HCV questionnaire before (week 0), at the end (week 12), and after DAA treatment at week 24. HRQL was measured in six different dimensions: physical health, emotional health, future uncertainty, intimate relationships, social health, and cognitive functions. Results: A total of 500 HCV patients receiving DAAs were enrolled; of them, 399 were included in the analysis (median age 57 years, 59% females). HRQL increased significantly between baseline, end of treatment, and week 24 for all dimensions (P < 0.001), more often for physical health in females compared to males (OR = 1.69, 95% CI = 1.1–2.5), for future uncertainty among people with diabetes (1.75, 95% CI = 1.05–2.9), and for cognitive functions among obese patients (OR = 1.98; 95% CI = 1.1–3.3). Improvement in HRQL was less common for intimate relations among females (OR = 0.47; 95% CI = 0.3–0.7) and in patients with cirrhosis (OR = 0.35, 95% CI = 0.1–0.7). Improvement in HRQL was consistently higher in < 60 years compared to ≥ 60 years patients, with a significant difference in social health (P < 0.001) and future uncertainty (P < 0.049) HRQL domains. Conclusion: HRQL improved with DAA therapy, a relation consistent across all HRQL dimensions up to 12 weeks after the end of treatment. [ABSTRACT FROM AUTHOR]