The role of corticosteroids in the prophylaxis of graft-versus-host disease (GVHD) is not well established. We have conducted a prospective, randomized, open-label, single-center study about the effect of adding methylprednisolone (MP) to the widely used prophylactic regimen consisting of cyclosporine A and methotrexate. A total of 108 consecutive patients treated with allogeneic bone marrow transplantation from an HLA-identical sibling donor for malignant blood disease were entered into the study; 53 patients were randomized to receive and 55 were randomized not to receive prophylactic MP. The dose of MP was 0.5 mg/kg on days 14 to 20, 1 mg/kg on days 21 to 34, 0.5 mg/kg on days 35 to 48, and thereafter the dose was slowly tapered and the administration discontinued on day 110. In the group given prophylactic MP, the incidence of acute GVHD was lower (19% vs 56%, P =.0001), there was a trend toward a lower incidence of chronic GVHD among low-risk patients (P =.06), and during the first 4 months the time spent at hospital was shorter and there were fewer infections. The total amount of MP given was similar in the study groups because of a higher incidence of acute GVHD and its treatment in the group of patients not given prophylactic MP. There were no significant differences between the study groups in relapse rate or survival. In conclusion, the addition of MP to the combination of cyclosporine and methotrexate markedly reduced the incidence of acute GVHD without causing untoward effects. The timing of corticosteroid administration is probably important for the efficacy.