Acute graft-versus-host disease (aGVHD) is a major barrier to successful bone marrow transplantation (BMT) with matched unrelated donors. Eight of eight recipients of matched unrelated donor BMT developed aGVHD. We used a regimen of high-dose methylprednisolone (5 mg/kg/day for 4 days with responders continuing on treatment, and dose escalation to 10 mg/kg/day for non-responders) as initial therapy of aGVHD. One patient died on the second day of steroid administration. Each of the seven remaining patients responded to methylprednisolone, five at the 5 mg/kg/day dose and two at the 10 mg/kg/day dose. Three of five patients developed flare of aGVHD during reduction of the corticosteroid dosage and died with aGVHD and infection. Two patients have undergone reduction of methylprednisolone at a modified rate without a flare. Infectious complications during methylprednisolone treatment were very common and contributed to the death of the three patients with flare of aGVHD. Four patients in whom aGVHD was in remission survived serious systemic infections. High-dose methylprednisolone is effective initial therapy for aGVHD associated with matched unrelated BMT, but is associated with a high risk of serious infections.