OBJECTIVES: Interferon-containing regimens for treatment of CH-C are associated with substantial side effects and significant impairment in HRQL. The aim of this study is to evaluate the effect of Interferon-free regimens on HRQL. METHODS: Three validated HRQL instruments, namely, Medical Outcomes Study-Short Form 36 (SF-36), CLDQ-HCV (Chronic Liver Disease Questionnaire-HCV) and FACIT-F (Functional Assessment of Chronic Illness Therapy-Fatigue) were administered to previously untreated CH-C patients (N=201) treated with interferon-free regimen (Sofosbuvir+Ribavirin) at baseline, during, and after treatment. Patients were randomized to receive 16 weeks of active treatment or 12 weeks of active treatment followed by 4 weeks of blinded placebo. Historical data for interferon containing regimens were available for all these questionnaires. RESULTS: Small decrements in most of the domains of all HRQL metrics were noted at weeks 4, 12, and 16 of active treatment regardless of the study arm (maximum observed decrements in HRQL summary scores between 3.3% and 8.8% compared to baseline, p<0.05). There were no differences between the study arms at all time points (p>0.05). These decrements were substantially better than historical data available for interferon-containing regimens (between 10.4% and 15.2% for the same scores, p<0.0001). By week 4 of follow-up after treatment, some of the social and emotional well-being-related domains of FACIT-F improved significantly compared to their own baseline (by 4.9-6.0%, p<0.05). At the end of 12-week follow-up, all those domains as well as domains of CLDQ-HCV (activity, emotional, worry, systemic domains) further improved (by 3.8-11.2%, p<0.05), while physical and functional well-being-related domains of FACIT-F and SF-36 returned to their baseline levels or improved moderately (by 3.1-8.3%, p<0.05). CONCLUSIONS: The impairment in HRQL in CH-C patients treated with an interferon-free regimen is minimal and diminishes soon after the end of treatment. This interferon-free regimen is associated with substantially better HRQL as compared to interferon-containing regimens.