A large percentage of HIV-infected patients are coinfected with hepatitis C virus (HCV). Current treatment available for HCV combines interferon and ribavirin therapy for 6 months or longer. Interferon is associated with numerous neuropsychiatric side effects including depression, cognitive impairment, anxiety, and irritability. The potential for developing depression is particularly concerning with coinfection because the incidence of depression is higher in the HIV-seropositive population than in the general population. This article discusses the mechanism and prevalence of interferon-induced depression and the debate regarding appropriateness of treatment in certain segments of the HIV population. The role of antidepressants as both treatment and a prophylaxis against interferon-related depression is reviewed. Nurses have a critical role in the care of HIV/HCV coinfected patients who are undergoing treatment with interferon and ribavirin. They both assess for treatment readiness prior to initiation and provide close monitoring for the development of neuropsychiatric disturbances while on therapy.