An increase in liver-related causes of death in HIV-positive patients who are coinfected with the hepatitis C virus (HCV) has been acknowledged over the last few years, particularly since the mid 1990s, when the natural history of HIV infection started to improve with the use of highly active antiretroviral therapy (HAART). Chronic hepatitis C is very common among HIV-infected patients who were infected through intravenous drugs use or contaminated blood products (e.g., hemophiliacs). The bidirectional interferences between HIV and HCV modify the natural history of both infections. Moreover, interactions between anti-HIV and anti-HCV drugs are of concern, and a lower response to anti-HCV therapy limits its benefit in HIV-coinfected patients. Although a slower HCV RNA decay is seen in coinfected patients after standard therapy is initiated with pegylated interferon plus ribavirin, the stopping rule at week 12 that is recommended for HCV-monoinfected individuals seems to be equally valid in HIV-positive patients. This finding is of great value, because it allows treatment to be offered in the absence of contraindication (e.g., low CD4 count, alcohol abuse, etc.) but discontinued as early as 12 weeks when no chances of cure are predicted, which saves costs and deleterious side effects. HAART therapy seems to temper somehow the negative impact exerted by HIV infection over HCV-related liver fibrosis. Liver transplantation is currently the best option for HIV-infected patients with end-stage liver disease. However, the management of patients on the waiting list and after transplantation carries significant new challenges. New anti-HCV drugs are urgently needed and new strategies with the currently available drugs need to be assessed to reduce the negative impact of hepatitis C in HIV-coinfected individuals.