The response to therapy of acute graft-versus-host disease (GVHD) is uncertain in recipients of unrelated donor (URD) bone marrow transplant (BMT). We analysed the outcome of treatment in 42 patients with moderate/severe acute GVHD. Initial therapy consisted of prednisone 60 mg/m2 orally daily for 7 days (n = 42), followed by anti-thymocyte globulin (ATG) 15 mg/kg i.v. twice daily for 8-10 doses after prednisone failure (n = 22). A clinical Stage Score for acute GVHD was determined initially and after 7, 14, 21, and 28 days of prednisone or ATG. Treatment failure represented worsening score after 7 days, involvement of a new organ or failure to improve after 14-28 days. Prednisone treatment led to 10 of 41 (24%) patients improving, while secondary therapy with ATG led to four of 21 (19%) improving. Of 42 patients treated, only nine (21%) achieved a complete and continuing response of acute GVHD by day +100. Neither age, diagnosis, recipient/donor gender status, histocompatibility nor GVHD prophylaxis regimen was associated with more frequent responses. Response to GVHD therapy was significantly correlated with survival at 100 days and 1 year post-BMT. We conclude that prednisone and ATG used for treatment of acute GVHD following URD BMT are associated with a high failure rate and that more aggressive therapy is warranted in these patients.