Acute and chronic rejection after kidney transplantation has long been exclusively attributed to cellular and vascular mechanisms. Modern immunosuppressive therapy, therefore, addresses the cellular immune system. Rising experiences in kidney transplantation in the last few decades have revealed that some types of rejection are refractory to the conventional immunosuppressive treatment. Humoral rejection. which has previously been reported as a crucial factor in hyperacute rejection, is now suspected to play also an important role in acute and chronic rejection. Acute humoral rejection (AHR) is characterized by immunohistochemical detection of C4d deposits in peritubular capillaries. As shown for other antibody-mediated diseases, such as some autoimmune diseases, plasmapheresis has been suggested to be an efficient therapeutic approach in AHR. We present four patients with C4d-positive AHR in the early phase after kidney transplantation. In three of the four patients, humoral graft rejection was successfully treated by plasmapheresis. Graft function was significantly improved with a stable long-term outcome. One patient lost the graft. Although the number of patients with C4d-positive AHR treated by plasmapheresis is limited, plasma exchange appears to be an efficient and powerful therapeutic approach to control humoral rejection.