Recent reports that co-infection with GB virus C (GBV-C) is associated with a reduced mortality in HIV-infected individuals, a slower progression to AIDS, and lower HIV viral loads, suggest a potential role of GBV-C as therapy for HIV infection. Although not known to cause any human disease, GBV-C was only recently discovered and prospective studies assessing long-term consequences of infection have not been completed. Our understanding of the host-viral interactions between humans and GBV-C is in its infancy. Further research into the intriguing relationship between GBV-C and HIV is needed before intentional inoculation of GBV-C into individuals infected with HIV should proceed. This essay explores the history of the once-popular treatment of paretic tertiary syphilis with the blood-borne pathogen Plasmodium vivax, providing a historical perspective on the current state of affairs between GBV-C and HIV. A brief review of GBV-C biology and human infection is followed by a discussion of the current challenges facing the use of this organism to treat HIV.