OBJECTIVE The results of trials using interleukin (IL)-2-based therapy in leukemia and after hematopoietic stem cell transplant suggest that such therapy could have an impact on preventing disease relapse in patients with hematologic malignancy who achieve a minimal disease state. The use of immunotherapy in the autologous transplant setting is modeled in part on the well-characterized immunotherapeutic effect of the graft-versus-tumor response in patients undergoing allogeneic transplantation. The graft-versus-tumor response, mediated by donor cells, contributes to the higher cure rates seen in patients undergoing allogeneic transplant for the treatment of a variety of hematologic malignancies, including acute and chronic myelogenous and lymphoblastic leukemia, myeloma, and lymphoma METHODS The literature was reviewed, and we relate our own clinical experience with IL-2 therapy in this setting. RESULTS Preclinical in vitro and animal data show a variety of leukemia cells are sensitive to autologous IL-2-activated effector cells. In addition, laboratory studies show that IL-2 can be used to activate antitumor cellular responses from bone marrow and peripheral blood without compromising hematopoiesis. Most importantly, in vitro studies show that chemoresistant malignant hematopoietic cells are sensitive to IL-2-induced cell death, thus emphasizing the lack of cross resistance to immunologic-based therapeutics. The results of phase I and II studies conducted in patients with acute myelogenous leukemia in first or subsequent remission suggest that autologous IL-2-activated cells may mediate an antitumor response and aid in preventing relapse after autologous transplantation. Clinical trials to determine the role of IL-2 after transplantation for the treatment of acute and chronic myelogenous leukemia, multiple myeloma, and lymphoma are ongoing. CONCLUSIONS These studies will help define the optimal dose and schedule of IL-2 and its role in augmenting therapeutic immune-mediated autologous responses.