Nearly all patients with hepatitis C virus (HCV) related end-stage liver disease who receive an orthotopic liver transplant (OLT) develop hepatitis C reinfection of the graft after transplantation. Most of these patients will progress to chronic hepatitis and 20-30% will experience a rapid progression to cirrhosis. It is unclear why it generally takes 20 or more years for progression to cirrhosis after the initial HCV infection, but as little as five years after OLT. Additionally, it is paradoxical that hepatitis C, which is thought to be immune-mediated, should advance more rapidly in patients who are immune suppressed. Rapid fibrosis progression post-transplantation is likely related to complex interactions between viral factors, host immune responses and induction and maintenance of immunosuppression for the prevention of graft rejection.