Chronic hepatitis C virus (HCV) infection is the main cause of liver cirrhosis and hepatocellular carcinoma in the western world and Japan. Liver transplantation (LT) is the only available treatment for patients with decompensated cirrhosis and for most individuals with hepatocellular carcinoma. Regretfully, hepatitis C recurs universally in HCV-infected individuals undergoing LT and the course of the disease is accelerated: liver cirrhosis develops in less than 5 years in around one third of HCV-infected liver transplant recipients. As a consequence, long-term graft and patient survival following LT are significantly reduced in HCV-infected patients as compared with other groups (alcohol, hepatitis B, cholestatic diseases). Recent data suggest that the events that trigger rapid disease progression take place during the first weeks following transplantation: activation of stellate cells and rapid fibrosis deposition in the graft are the key players in recurrent hepatitis C. From a theoretical point of view there are two different strategies to prevent HCV-induced graft damage: 1) prevention of HCV infection by blocking viral entry into hepatocytes and 2) early identification of rapid “fibrosers” to start antiviral treatment before severe hepatitis C develops. To achieve the first aim (immune prophylaxis), it is crucial to understand the very early HCV kinetics. For this purpose, we plan to perform a thorough analysis of HCV kinetics during surgery and the first hours following LT, including a detailed investigation of HCV receptor expression and HCV envelope protein mutations that could facilitate viral entry. To achieve the second aim, we need to identify at a very early stage those patients at risk of rapid fibrosis progression. For this purpose, we will search for early markers of stellate cell activation and hepatocyte damage in liver biopsies. Moreover, we will take advantage of serum samples of liver transplant recipients with very high viral load to explore if serum-derived HCV could replicate in cell culture. We believe that our project will be helpful in dissecting the early steps of HCV infection and its consequences in the liver graft. If we succeed in our aims, our data would facilitate the design of therapeutic studies aimed at preventing severe hepatitis C recurrence.