<sec> <b>Objectives</b> <p>To evaluate the impact of 3 treatment regimens upon health-related quality of life and work productivity using patient-reported outcomes (PROs) in chronic hepatitis C infected patients: sofosbuvir (SOF) + daclatasvir (DCV); SOF + DCV + ribavirin (RBV); SOF + simeprevir (SMV).</p></sec> <sec> <b>Methods</b> <p>4 questionnaires were used to evaluate PROs before, during and after treatment: Short Form-36 (SF-36), Chronic Liver Disease Questionnaire (CLDQ) - hepatitis C virus (HCV), Work Productivity and Activity Index, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F).</p></sec> <sec> <b>Results</b> <p>Of the global sample of 55 patients included in this study; SOF + DCV (<italic>n</italic> = 10); SOF + DCV + RBV (<italic>n</italic> = 29); SOF + SMV (<italic>n</italic> = 16) all had a statistically significant improvement in SF-36, CLDQ and FACIT-F scores during and post-treatment. No statistically significant differences in the PRO questionnaire values were observed between the distinct treatment regimens. The SOF and SMV patient groups presented higher mean PRO variations during and post-treatment, compared to the other groups: SF-36 functional capacity (16.1); SF-36 mental health (21.4); CLDQ activity (1.8); CLDQ emotional function (1.2); FACIT-F physical well-being (8.0); Total FACIT-F (21.6).</p></sec> <sec> <b>Conclusion</b> <p>Treatment with SOF + DCV, with or without RBV, results in an improved PRO similar to treatment with SOF + SMV in chronic hepatitis C patients.</p></sec>