Individuals at risk of HIV are concomitantly at risk of acquiring parenterally or sexually transmitted viruses. Multiple hepatitis co-infection (HBV+HCV; HBV+HDV; HBV+HDV+HCV) has not been systematically sought after in the large cohorts of HIV-infected patients, but has been reported in 0.4% to more than 50% of patients. HIV-infected patients with multiple hepatitis have a higher rate of liver-related morbidity and mortality than patients with HIV infection alone or with a single hepatitis co-infection. The degree of immunodepression is an important factor in liver disease progression. Since GBV-C virus is transmitted parenterally or by sexual contact, a high prevalence was found in chronic hepatitis C and in HIV-infected patients. Patients with multiple hepatitis have been excluded from randomised therapeutic trials of viral hepatitis in HIV-infected and HIV-negative patients. Thus, the therapeutic approach is based on the results of a small series and empirically oriented toward the prevailing infection. HIV-infected patients should be tested for hepatitis B, C and D systematically and hepatitis B vaccination should be considered for those with HCV co-infection and absence of HBV markers. Studies are needed to assess treatment strategies.