An association between hepatitis C virus infection and neuropsychiatric symptoms has been proposed for some years. A variety of studies have been undertaken to assess the nature and severity of these symptoms, which range from fatigue and depression to defects in attention and verbal reasoning. There is evidence of mild neurocognitive impairment in some patients with HCV infection, which is not fully attributable to liver dysfunction or psychosocial factors. Further evidence of a biological cerebral effect has arisen from studies using magnetic resonance spectroscopy; metabolic abnormalities correlate with cognitive dysfunction and resemble the patterns of neuroinflammation that have been described in HIV infection. Recent research has suggested that, in common with HIV infection, HCV may cross the blood brain barrier leading to neuroinflammation. Brain microvascular endothelial cells, astrocytes and microglia may be minor replication sites for HCV. Importantly, patient reported outcomes improve following successful antiviral therapy. Further research is required to elucidate the molecular basis for HCV entry and replication in the brain, and to clarify implications and recommendations for treatment.