Cyclosporine and methotrexate at standard doses (15 mg/m2 on day 1 and 10 mg/m2 on days 3, 6, and 11, total 45 mg/m2) are effective in the prophylaxis of acute graft-vs.-host disease. However, the combination has significant early toxicities with delayed engraftment, increased mucositis, and hepatotoxicity. We modified the combination by adding single-dose methylprednisolone and lowered the total dose of methotrexate to 35 mg/m2 (5 mg/m2 on days 1, 3, and 6, and then 10 mg/m2 on days 11 and 18) and then to 20 mg/m2 (5 mg/m2 on days 1, 3, 6, and 11) in an attempt to decrease these side effects in two sequential consecutive groups of patients. We demonstrated that the modified regimens maintained the efficacy with reduced toxicities. The rate of engraftment was comparable to cyclosporine alone and the hepatotoxicity was reduced with reduced doses of methotrexate. Factors such as early immunosuppression of the host, intravenous immunoglobulin, the timing of steroid administration, nucleotide free diet and germ free environment may contribute to the effectiveness of the combination and permit reduction of methotrexate dose.