HCV genotype 5 (HCV-5) is the least known HCV genotype. It is found mainly in South Africa and in restricted areas of Belgium, Spain, France, Syria and Greece. Sporadic cases are reported worldwide. The main modes of transmission are blood transfusion and iatrogenic causes. Little is known about its origin, but various studies have elucidated its spread worldwide. In endemic areas, patients infected with HCV-5 are on average older and have a higher viral load and more advanced fibrosis than those infected with non-HCV-5 genotypes. The current standard of care for HCV-5 chronic infection is 48 weeks of dual therapy with pegylated interferon plus ribavirin. ‘Favourable’ Il28B polymorphisms are not associated with higher sustained viral response rates. Assessment of shorter duration of therapy is made difficult by the lack of identifable baseline predictors of response. Whilst there are in vitro data showing good activity of some direct-acting antivirals and of host-targeted agents against HCV-5, no clinical trials of these molecules have yet started.