The GB virus C is a common non-pathogenic virus, member of the Flaviviridae family with worldwide distribution. Favorable clinical course and reduced mortality among HIV-infected patients was demonstrated by several studies with patients co-infected with the GB virus C (GBV-C). This potential benefit of GBV-C has been demonstrated in the pre-HAART and post-HAART eras; however, this effect was not observed in all studies and the discrepancy may be due to changes during the course of HIV infection, characteristic of the cohort, and the degree of therapeutic response. The GBV-C has been found to decrease HIV replication in in vitro models, highlighting the interference of persistent GBV-C viremia. The mechanism of the beneficial effect of GBV-C appears to be mediated by changes in the cellular immune response, and elucidation of putative protective effects of GBV-C in HIV co-infection could potentially identify novel targets for anti-HIV agents.