CAMPATH-1 (CDw52) antibodies recognize a very small lipid-anchored glycoprotein that is expressed on the surface of human lymphocytes. They are remarkably lytic with human complement. In addition, CAMPATH-1G (rat IgG2b) and CAMPATH-1H (human IgG1) bind to human Fc receptors and are very effective for cell lysis in vivo. CAMPATH-1M (rat IgM) and CAMPATH-1G have been used to control GVHD and graft rejection in bone marrow transplantation by depletion of the T cells of the donor and recipient. Depletion of donor T cells alone gave excellent control of GVHD but up to 20% of the patients transplanted from HLA-matched siblings, and 51% of those transplanted from nonsibling donors, experienced graft failure caused by immunological rejection. Graft rejection could be partly overcome by additional immunosuppression either with CsA or total lymphoid irradiation (TLI). More effective was the use of CAMPATH-1G in vivo to deplete residual host lymphocytes. Preliminary results from current protocols of antibody depletion give two year actuarial leukemia-free survival as good as or better than similar studies with conventional GVHD prophylaxis, as well as a decreased morbidity from chronic GVHD, although engraftment was delayed by about 5 days. We propose that prophylactic T cell depletion with CAMPATH-1 antibodies is a simple and valid alternative to drug-based immunosuppression that may be particularly applicable to patients with acute leukemia or nonmalignant diseases transplanted from HLA-matched siblings as well as any patients transplanted from unrelated donors. Future developments of antibody-based immunosuppression may allow the extension of marrow transplantation for tolerance induction to organ transplants or in autoimmune diseases.