OBJECTIVES: To examine the value of adding simeprevir (SMV) to peginterferon and ribavirin (PR) for treatment of chronic hepatitis C virus infection using patient-reported outcomes (PRO) and their concordance with virology endpoints and adverse events (AEs). METHODS: Patients rated severity of fatigue (FSS), depressive symptoms (CES-D), and impairment in functioning (WPAI:HepC Productivity, Activity, Absenteeism) at baseline and throughout treatment/follow-up in three randomized, double-blind trials comparing addition of SMV or Placebo (PBO) during initial 12 weeks of PR treatment. PR was administered for 48 weeks (PBO group) and either 24 or 48 weeks (SMV group) (response-guided therapy [RGT]). Analysis of pooled data from the trials using a piecewise-linear mixed model compared the area-under-the-curve from baseline to Wk60 (AUC60) between SMV/PR and PBO/PR for each PRO score. Subgroup analyses evaluated impact of Sustained Virologic Response 12 weeks post-treatment (SVR12), fibrosis level, and RGT on PRO scores.  RESULTS: Of 1178 patients studied, analyses included 768 SMV/PR- and 393 PBO/PR-treated patients. 87.5% of the SMV/PR group met RGT and completed treatment in 24 weeks. Fatigue and anaemia AEs were comparable in both groups but FSS scores show clinically important increases in fatigue, lasting 6.9 weeks longer with PBO/PR (p <0.001). No significant differences were observed for Absenteeism. Mean scores for all other PRO endpoints worsened from baseline to Wk4 in both groups and remained impaired to Wk24 (SMV/PR) and Wk48 (PBO/PR), resulting in significantly lower AUC60and fewer weeks with clinically important worsening scores with SMV/PR. PRO scores indicated better outcomes for patients who met RGT criteria or achieved SVR12; differences in PRO scores associated with fibrosis level were only observed in the PBO/PR group. CONCLUSIONS: Greater efficacy of SMV/PR enabled reduced treatment duration and less time with PR-related side effects without adding to the severity of side-effects during treatment.