While HCV was initially believed to uniformly cause liver inflammation with the consequence of liver cirrhosis in most of the infected patients, prospective studies have shown a much lower than expected rate of cirrhosis in patients infected for more than 20 years. However, a new problem associated with hepatitis C virus infection is emerging. This is the development of sometimes disabling fatigue. While many other viruses of the flaviviridae cause encephalitis, the most closely related virus to HCV in humans, the GB Virus C seems not to be associated with fatigue. Thus the mechanism for the development of fatigue in HCV infection seems specific for HCV. Delineating the mechanism will be a first step to develop treatment option for this currently untreatable impairment.