One third of HIV-infected individuals worldwide suffer from chronic hepatitis C virus (HCV) infection. Two main reasons justify considering HCV therapy as a priority in HIV-coinfected patients. First, these patients have more rapid liver disease progression, and second, they have a higher risk of developing hepatotoxicity following the initiation of antiretroviral therapy. Unfortunately, HCV therapy is associated with lower response rates and higher rate of side effects in HIV-coinfected patients. However, recent evidence suggests that when HCV therapy is administered adequately (to optimal candidates; using full doses of ribavirin; at least for 12 months irrespective of the HCV genotype; and with satisfactory drug adherence), treatment responses may not differ much from those seen in HCV-monoinfected individuals. Treatment should be considered up front in antiretroviral-naive subjects with stable HIV infection. In patients already on antiretroviral therapy, HCV therapy should not be administered before replacing didanosine by another antiretroviral, given the increased risk of mitochondrial toxicities. If possible, zidovudine should be avoided as well, given the high risk of anemia. The histological information provided by either non-invasive procedures (FibroScan, Fibro-test, etc.) or liver biopsy is useful but should not be considered as mandatory before prescribing HCV therapy. In summary, liver disease associated to HCV is a growing problem among HIV-positive individuals. The relatively low efficacy of current anti-HCV medications and their low tolerability clearly indicated the need for new drugs with more potent and direct antiviral activity against HCV.