Neuropsychiatric symptoms are commonly associated with chronic hepatitis C virus infection (HCV). The aim of this review of the literature was to evaluate the prevalence of depression in patients with hepatitis C, as well as the proposed etiopathogenic models. A review of the literature was undertaken using the complete search strategy devised by the Cochrane Collaboration Review Group for Depression, Anxiety and Neurosis. All studies but one have shown that major depression in chronic HCV patients is significantly more common than in the general population (reported rates from 5.7% and 45%), being related with illness perception, functional disability, impaired quality of life, fatigue severity, and the presence of psychiatric comorbidity. The mechanism by which depression is related to Hepatitis C is still poorly understood. Authors address some possible mechanisms, such as the psychological impact of the knowledge that one has been infected with HCV and the direct effects of the virus itself on the Central Nervous System (eg. cytoquines).