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/m² 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.