OBJECTIVES: Pegylated-interferon/ribavirin (PR) is commonly used to treat HCV genotype 1 (G1) -infected patients, both as dual therapy or triple therapy, combined with a direct-acting antiviral (DAA). PR-based treatments are associated with high levels of toxicity and decreased QoL. Adding simeprevir as DAA to PR reduces duration of PR-therapy and increases significantly the proportion of patients reaching viral response (VR). The objective of this analysis was to explore the impact of duration of PR therapy and of having VR on the level of impairment of QOL and other patient-reported outcomes (PRO). METHODS: Longitudinal QoL/PRO outcomes were analyzed from three randomized clinical trials comparing PR+simeprevir with PR in treatment-naïve HCV-G1 patients: PILLAR (n=316); QUEST-1 (n=394) ; QUEST-2 (n=391).  Early responders in the simeprevir arm were allowed to stop PR-therapy at 24 weeks, instead of 48 week PR-therapy.  A mixed-effects model was fitted, including age, gender, baseline fibrosis status, time, treatment interaction between time and treatment  as covariates, and PR-therapy and viral response as binary time-varying covariates (viral load </≥25 IU/ml).  A model was fitted by trial for the EQ-5D valuation index (VI) and visual analog scale (VAS), the Fatigue Symptom Severity scale (FSS) and the Center for Epidemiologic Studies Depression Scale (CES-D). RESULTS: Shortened PR-therapy positively impacted all PRO-endpoints consistently across all studies (p-values ranging between <0.0001 and 0.025). The estimated mean for the positive impact on EQ5D-VI were 0.08 (p=0.0001), 0.05 (p=0.025) and 0.08 (p=0.0005) for PILLAR, QUEST-1 and QUEST-2, respectively.  Having VR only had a minor positive impact, and was not statistically significant for most endpoints/trials. Female patients had significantly lower values for EQ-5D-VI, and numerically lower values for all other QoL-measures. CONCLUSIONS: These findings suggest that short-term QoL impairment due to HCV-therapy is driven more by the longer duration of PR-therapy than by not obtaining VR.