INTRODUCTION: Interferon (IFN)-free regimens for the treatment of chronic hepatitis C have shown high rates of sustained virological response (SVR) and improved patient-reported outcomes (PROs). The aim of this study was to evaluate the health-related quality of life (HRQoL) and fatigue of patients with chronic hepatitis C (HCV) treated with IFN-free direct-acting antiviral (DAA) agents that achieved SVR following treatment and identify the predictive factors related to HRQoL. METHODS: Prospective cohort study that included patients with HCV treated with DAA who obtained an SVR. The patients answered three self-reported questionnaires (PROs): Short Form 36 (SF-36), the Chronic Liver Diseases Questionnaire (CLDQ), and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire at baseline, weeks 6 and 12 of treatment, and at 12 weeks after therapy. Patients were treated with DAA with or without ribavirin (RBV). The PRO scores were compared using analysis of variance (ANOVA). A comparison of PROs and serum hemoglobin levels was performed between the group that used ribavirin and the one that did not use ribavirin using the t student test. Predictive factors were calculated using a multiple linear regression model. RESULTS: Among the 113 patients selected, 105 presented an SVR and were included in the study, in which, 54% men, 80% genotype 1, 44% cirrhosis and 46% with RBV. At 12 weeks after the end of treatment, there was a significant improvement in the scores of the patient self-reports (PROs) when compared with baseline for the CLDQ (+10.52%, p<0.001), SF-36-Physical Summary (+19%, p<0.001), and FACIT (+17.34%, p<0.001). Patients who used RBV had worse PROs and serum hemoglobin levels compared to the group that did not use RBV (p<0,05). As predictors of worsening of the PROs we had the presence of diabetes mellitus, liver cirrhosis and HIV co-infected. CONCLUSION: Patients treated with IFN free regimens presents significant improvement in PROs. The presence of diabetes mellitus, cirrhosis, and HIV co-infected has a negative effect on HRQoL before, during and after treatment of hepatitis C. The addition of ribavirin to the antiviral regimens used compromises the HRQoL indexes during antiviral therapy.