OBJECTIVES: Hepatitis C virus (HCV) is the most common cause of chronic liver disease in Japan. Additionally, HCV infection causes debilitating extrahepatic manifestations such as chronic fatigue with negative impact on patients’ health-related quality of life and work productivity. Fatigue and vitality impairment have not been assessed in Japanese patients with CHC. METHODS: Short Form-36 (SF-36) was administered before, during and after treatment to Japanese CHC patients (GT1) treated with ledipasvir/sofosbuvir±ribavirin (LDV/SOF±RBV) for 12 weeks and to HCV genotype 2 treated with SOF+RBV for 12 weeks in clinical trials. Self-reported history of clinical fatigue was documented by investigators. The vitality (VT) domain of SF-36 was used to estimate fatigue construct. RESULTS: Fukuharaet al., 1998], p<0.0001). By the end of 12 weeks of treatment, a significant improvement of vitality from baseline was noted only in CHC patients who received LDV/SOF (+3.2 points, p=0.004). Achieving SVR-12 was associated with improvement of vitality scores in all CHC patients regardless of the treatment regimen (+1.8 points, p=0.007). In multivariate analysis, lower vitality scores at multiple time points were predicted by presence of cirrhosis, sleep disorders, and use of RBV during treatment (all p<0.02). CONCLUSIONS: Although not captured by clinical assessment of “fatigue”, vitality impairment is common in Japanese patients with CHC. This impairment improves by viral eradication while receiving interferon-free regimens.