Few data are available about the treatment of chronic infection with hepatitis C virus (HCV) in HIV-infected persons with active drug or alcohol addiction and psychiatric disorders. We report the case of a 42-year-old man who entered care with a CD4+ cell count of 78/microL but was reluctant to take many of the available antiretroviral agents. For many years, periods of sobriety and good adherence to antiretroviral medications were interspersed with relapses to heroin, cocaine, and alcohol use as well as episodes of overdose, major depression with psychiatric hospitalization, incarceration, and discontinuation of antiretroviral medications. After 4 years of HIV primary care, the patient was stabilized to begin therapy for hepatitis C with pegylated interferon and ribavirin with the support of a multidisciplinary team. After starting treatment for hepatitis C, the patient achieved an early virologic response and continues to have an undetectable HCV RNA level by polymerase chain reaction testing and 100% adherence to on-site pegylated interferon injections, without adverse events related to his addiction or psychiatric symptoms. This case suggests that HIV-HCV-coinfected persons with the common comorbidities of polysubstance dependence and psychiatric illness may effectively and safely undergo pharmacotherapy for hepatitis C with appropriate support.