The current outcome typical of hepatitis C virus-infected liver recipients after a first transplant is worrisome. Prophylaxis with antivirals has yielded a low rate of success. Without effective prophylaxis, the attention should be focused on the one factor that can be controlled: immunosuppression. A summarized review of the impact of immunosuppressive agents used for the past few years is presented in the context of hepatitis C virus recurrence. Steroids have been blamed for years as the main culprit in the higher incidence of hepatitis C virus recurrence reported in some series. New experience with these agents may prove the opposite. Purine synthesis inhibitors such as azathioprine and mycophenolate mofetil may help to reduce the incidence of hepatitis C virus recurrence after liver transplantation, although further studies are needed to confirm these recent reports. Antilymphocytic therapy with monoclonal or polyclonal antibodies does not seem to be harmful when used at induction. Most reports have analyzed these agents in the context of steroid-resistant rejection, a confounding factor in many studies. The calcineurin-inhibitors, cyclosporine and tacrolimus, appear with similar incidences of hepatitis C virus recurrence and their current use is only center-dependent. Newer agents like sirolimus and antibodies against IL-2 receptors still need to pass the test of time before firm recommendations can be given in any sense. Larger, randomized studies will finally answer questions concerning the best immunosuppressive agent combinations for treating the high-risk hepatitis C virus-infected population of liver transplant recipients.