To define high-risk acute graft-versus-host disease (GVHD) at onset, we examined the initial GVHD stage and grade of 864 patients at the University of Minnesota who received uniform therapy with prednisone 60 mg/m(2) per d. We compared the prognostic utility of the Minnesota (MN; modified from Consensus) versus Center for International Blood and Marrow Transplant Research (CIBMTR) GVHD organ stage-derived grading systems. As neither GVHD grading system optimally predicted outcomes, a novel acute GVHD risk score was devised by combining the MN and CIBMTR systems. Using multiple regression analysis, we could dichotomize patients into high risk (HR, n = 86) acute GVHD with initial grade IIIC, IIID or IVD who were less likely to respond to steroid therapy by day 28 [relative risk (RR), 0·3, P < 0·001] and had a higher risk for transplant-related mortality (RR, 2·0, P < 0·001) than patients with standard risk (SR, initial grade IA-IIIB, n = 778) GVHD. Using this novel acute GVHD Risk Score, HR GVHD is either skin stage 4, lower gastrointestinal (GI) stage 3+, liver stage 3+, or skin stage 3 and lower GI or liver stage 2+ GVHD. Patients with HR acute GVHD have a poor prognosis, require alternative initial therapy and should be the focus of novel therapeutic trials.