In numerous studies of symptoms in patients with chronic hepatitis C there has been no systematic assessment of both fatigue and extrahepatic manifestations. Our objective was to assess the prevalence of fatigue in patients with hepatitis C virus (HCV) infection, and to identify associations between fatigue and clinical and biological hepatic and extrahepatic manifestations. We studied 1614 patients. Data were prospectively recorded during the first visit of patients infected with HCV and the prevalence of fatigue and its association with dermatological, rheumatological, neurological and nephrological manifestations; diabetes; arterial hypertension; auto-antibodies, and cryoglobulinaemia were assessed. Then, using multivariate analysis, we identified demographic, biochemical, immunological, virological, and histological factors associated with the presence of fatigue. Fatigue was present in 53% of patients (95% confidence interval 51-56). In 17% of patients (95% confidence interval 15-19) fatigue was severe, impairing activity. Five other extrahepatic manifestations had a prevalence above 10% including, in decreasing order: arthralgia, paresthesia, myalgia, pruritus, and sicca syndrome. In univariate and multivariate analyses, fatigue, in comparison with the absence of fatigue, was associated with female gender, age over 50 years, cirrhosis, depression and purpura. Independent of these associations, fatigue was associated with arthralgia, myalgia, paresthesia, sicca syndrome and pruritus. The prevalence of fibromyalgia (as defined by the association of fatigue with arthralgia or myalgia) was 19% (95% confidence interval 17-21). There was no significant association between fatigue and the following characteristics: viral load or genotype, alcohol consumption, abnormal thyroid function, and type and level of cryoglobulinaemia. Hence, fatigue is the most frequent extrahepatic manifestation in patients infected with HCV. Fatigue is independently associated with female gender, age over 50 years, cirrhosis, depression and purpura.