To develop a novel acute graft-versus-host disease (GVHD) risk score, we examined the GVHD clinical stage and grade of 1723 patients at the onset of treatment with systemic steroids. Using clinical grouping, descriptive statistics and recursive partitioning, we identified poorly responsive, high-risk (HR) acute GVHD by the number of involved organs and severity of GVHD at onset. The overall response (complete response/partial response) rate 28 days after initiation of steroid therapy for acute GVHD was lower in the 269 patients with HR-GVHD than in the 1454 patients with standard risk (SR)-GVHD (44% [95% confidence interval (CI) 38% to 50%] versus 68% [95% CI, 66% to 70%], P < .001). Patients with HR-GVHD were less likely to respond at day 28 (odds ratio [OR], .3; 95% CI, .2 to .4; P < .001) and had higher risks of mortality (relative risk, 2.1; 95% CI, 1.7 to 2.6; P < .001) and transplant-related mortality (relative risk, 2.5; 95% CI, 2.0% to 3.2%, P < .001) than patients with SR-GVHD. This refined definition of acute GVHD risk is a better predictor of response, survival, and transplant-related mortality than other published acute GVHD risk scores. Patients with HR-GVHD are candidates for studies investigating new treatment approaches. Likewise, patients with SR-GVHD are candidates for studies investigating less toxic therapy.