BACKGROUND AND AIMS: This study evaluated the clinical and non-clinical determinants of health-related quality of life (HRQoL) associated with untreated chronic hepatitis C (CHC) in France. METHODS: From 01/2014 to 01/2015, untreated CHC patients were invited to complete a questionnaire including EQ-5D utility instrument and two visual analogue scales (VAS) measuring overall health and fatigue in three French centers (Paris, Lille and Montpellier). Answers were analyzed in mixed models (taking into account the clustering effects of centers and physicians). RESULTS: Five hundreds and five patients were enrolled: 52% males; the mean age was 54; 41% had BMI>25; 64% had genotype 1; 36% were at the stage of severe fibrosis (F3-F4); 38% had severe comorbidities other than liver-related. In the univariate analysis, EQ-5D utility was associated with socio-demographic variables as age, place of birth, education, and employment; CHC-related variables as conditions of HCV screening and severity of fibrosis; CHC-unrelated variables as comorbidities other than CHC, being overweight, and psychiatric disorders; feelings about CHC disease as perception of progression, lack of information on CHC and its treatments, and entourage's feeling. In multivariate analysis, EQ-5D utility was affected by not being in employment (0.72 vs. 0.80), having severe comorbidities other than CHC (0.72 vs. 0.79), being overweight (0.73 vs. 0.78), and feeling worried about CHC progression (0.66 vs. 0.72-0.84). Similar results were found for the VAS. CONCLUSIONS: The presence of severe comorbidities and worrying about CHC progression, but not stage of fibrosis, seem to alter significantly EQ-5D health utility in CHC French patients.