Summary. Hepatitis C virus (HCV) infection is a major cause for liver transplantation worldwide. Still, HCV re-infection of the graft occurs in almost all cases. Most liver transplant recipients experience episodes of graft hepatitis associated with fibrosis progression and graft failure. Clinical management of graft hepatitis can be challenging as in addition to rejection and HCV-induced hepatitis various other factors might be involved including toxic liver injury, steatohepatitis, ischaemic bile duct lesions or infections with other pathogens. Treatment options are often contradictory for different causes of graft hepatitis, and the role of distinct immunosuppressive drugs has been discussed controversially. Corticosteroids increase the infectivity of HCV by altering expression levels of entry factors and other immunosuppressive agents may have diverse effects on HCV replication and fibrosis progression. Interferon alpha-therapy of hepatitis C shows limited efficacy and tolerability in liver transplant recipients and may also cause rejection. In this review we summarize the current knowledge on mechanisms of liver injury in post-transplant hepatitis C, discuss the pros and cons of immunosuppressive agents in this specific setting and describe potential novel approaches to prevent HCV reinfection.