OBJECTIVES: Fatigue is the most common side-effect of treatment for chronic hepatitis C virus (CHC) infection with peginterferon-α and ribavirin (PR).  Adequacy of the Fatigue Severity Scale (FSS) total scores for evaluating fatigue from the patients’ perspective in CHC trials was assessed using blinded data from two CHC clinical trials. METHODS: 386 treatment-naïve patients (PILLAR) and 462 treatment-experienced patients (ASPIRE) were randomized to receive simeprevir (TMC435), a potent, oral, once-daily, investigational HCV NS3/4A protease inhibitor in Phase III clinical development and PR or placebo/PR. Patients completed the FSS and EQ5D in their native language throughout the 72 week trials.  Reliability of the FSS was evaluated using Cronbach’s co-efficient a at Week 24 (internal consistency reliability) and intraclass correlation (ICC) between FSS at Weeks 12 and 24 in stable patients (<0.5 g/dL change in hemoglobin between Weeks 12/24).  Concurrent validity was assessed as correlation with the EQ5D visual analog scale (VAS).  Known-groups validity of FSS scores was assessed using mean comparison by levels on the EQ5D daily activity item and by clinician-rated fatigue AEs at Week 24.  Distribution- and anchor-based methods identified values representing a meaningful change in individual and mean FSS scores. RESULTS: FSS scores were highly reliable (Cronbach’s α = 0.95, 0.96 and ICC: 0.74, 0.86 for PILLAR and ASPIRE, respectively).  Concurrent validity (correlation of FSS and EQ5D VAS = -0.63, -0.66) and known groups validity (mean FSS scores by EQ5D daily activity levels or fatigue AEs severity (p <0.05) were confirmed.  Analyses suggest that a meaningful change in mean FSS scores ranges from 0.33-0.82, and that a 1 point change is a conservative indicator of an important within-subject change in FSS score CONCLUSIONS: The Fatigue Severity Scale provides reliable and valid assessment and quantification of fatigue for clinical trials in patients with CHC infection.