Hepatitis C virus (HCV) and HIV-1 are often harbored in the same host, establishing chronic infections typically characterized by persistent viremia. HIV-1 has deleterious effects on the course of HCV infection by increasing the rate of HCV viral persistence, quantitative HCV RNA levels, and ultimately the liver fibrosis progression rate. Conversely, HCV may blunt the effectiveness of immune reconstitution following antiretroviral therapy in HIV-infected individuals. Better understanding of the pathogenic mechanisms underlying these clinical observations may facilitate novel and effective therapeutic interventions that tackle the clinical conundrums raised by HIV/HCV coinfection.