Acute graft-versus-host disease is a major problem in allogeneic bone-marrow transplantation. We performed a randomized study to compare the effectiveness of two regimens in the prevention of acute graft-versus-host disease. Thirty-five patients received methotrexate alone, and 32 received methotrexate, antithymocyte globulin, and prednisone. Of the patients who received methotrexate alone, 48 per cent had acute graft-versus-host disease, as compared with 21 per cent of those who received methotrexate, antithymocyte globulin, and prednisone (P = 0.01). The age of the recipient was a significant factor in the development of acute graft-versus-host disease: Older patients had a higher incidence of the disease (P = 0.001). We conclude that the combination of methotrexate, antithymocyte globulin, and prednisone significantly decreased the incidence of acute graft-versus-host disease and should be used to prevent this disorder in patients receiving allogeneic marrow transplants. (N Engl J Med. 1982; 306:392–7.), GRAFT-VERSUS-HOST disease continues to be a major cause of morbidity and mortality after allogeneic bone-marrow transplantation.1 Several methods have been used in attempts to prevent graft-versus-host disease, including methotrexate therapy after transplantation,1 in vitro treatment of the donor's marrow with anti-T-cell globulin2 or monoclonal antibody,3 and immunosuppression with cyclosporin4,5 or antithymocyte globulin6,7 after transplantation. Our report describes the results of a randomized trial comparing two prophylactic regimens designed to prevent acute graft-versus-host disease in patients receiving marrow transplants at the University of Minnesota. Specifically, the study compared the effectiveness of methotrexate alone with that of methotrexate in combination with antithymocyte.