Fatigue is a main patient reported outcome of chronic hepatitis C (HCV) infection; yet its contributors are unknown. Objectives: The study (1) evaluated fatigue predictors, (2) tested the mediating role of fatigue cognitions, (3) screened for sleep disorders, and (4) explored fatigue from patients’ perspectives. Participants: Both sexes (age>18 years, N = 115) with chronic HCV infection. Design: Cross-sectional. Results: Sixty percent reported severe fatigue (FSS≥4). Fatigue perceptions were the main predictors of fatigue (ß=.58, bias corrected CI = .070-.163). Fatigue perceptions mediated the relationship between comorbidities and fatigue. Half of the sample reported clinically significant symptoms of insomnia and/or sleep apnea. Eight main fatigue themes were endorsed by the participants. Conclusions: Fatigue and sleep disorders were clinically significant issues. Fatigue cognitions may contribute to severe fatigue outcomes. Significance: Integrating the findings into existing sleep and fatigue treatments could improve clinical outcomes.