GB virus C (GBV-C) is a single stranded positive sense RNA virus, which is a member of the Flaviviridae. It has a close sequence homology and genomic organisation to hepatitis C virus (HCV). However, unlike HCV it is not hepatotrophic. GBV-C replicates within cells of the haemopoietic lineage, in particular lymphocytes. No disease has been associated with GBV-C infection but co-infection with human immunodeficiency virus (HIV) leads to improved morbidity and mortality for the HIV infected individual and slows progression to acquired immunodeficiency syndrome. This potential benefit of GBV-C has been demonstrated in the pre and post highly active anti-retroviral treatment (HAART) eras. GBV-C has been found to decrease HIV replication in in vitro models. The mechanism of the beneficial effect of GBV-C appears to be mediated by alterations in the cellular immune response, the details of which remain unclear. Despite this, there continues to be controversy regarding the influence of GBV-C on HIV as several reports have questioned the beneficial effect. GBV-C does not appear to influence liver related disease in subjects co-infected with HCV or hepatitis B virus (HBV). Combination of HIV and HCV leads to accelerated liver disease. The influence of GBV-C in this situation is yet to be determined. Elucidation of the putative protective effect of GBV-C in HIV co-infection could potentially identify novel targets for anti-HIV therapeutics and lead to the development of disease modifying vaccines.