Chronic rejection is still the major limitation of long-term outcome of heart transplant recipients. Several recent studies demonstrated that a not negligible proportion of chronic allograft rejection episodes are not only mediated by T-cell response but also triggered by pre-transplant and de novo post-transplant donor-specific alloantibodies. This points at a fundamental role of humoral immune response mechanisms that contribute to early and late graft failure. This type of rejection is an unsolved problem solid organ transplantation because current immunosuppressive regimens are generally intended to interfere in T-cell signalling pathways. Various options for the removal of circulating alloantibodies and the prevention of alloantibody formation by B-cell depletion have been described. Nevertheless, effective standardized schemes for the treatment of antibody-mediated graft rejection have to be defined. We present a heart transplant recipient with sustained antibody-mediated graft rejection who was successfully managed with a combination treatment consisting of 3 cycles of immunoadsorption and a single-dose administration of the anti-CD20 monoclonal antibody rituximab.