Acute graft-versus-host disease (GVHD) is a major limiting factor in allogeneic hematopoietic stem cell transplantation (HSCT), and the timing of acute GVHD may affect patient outcomes. We evaluated the incidence, risk factors, clinical manifestations, and outcomes of hyperacute GVHD, defined as that occurring within 14 days after transplantation, among 809 consecutive HSCTs at the University of Texas M. D. Anderson Cancer Center. Of 265 patients with grade II-IV acute GVHD, 27% had biopsy-proven hyperacute GVHD. Skin involvement was significantly more common (88% versus 44%) and more severe (stage III-IV, 88% versus 66%) in the hyperacute group compared with acute GVHD diagnosed after day 14. On multivariate analysis, significant risk factors for hyperacute GVHD included a mismatched related or matched unrelated donor, a myeloablative conditioning regimen, more than 5 prior chemotherapy regimens, and donor-recipient sex mismatch. Hyperacute GVHD was associated with a significantly lower response rate to first-line therapy and a higher rate of nonrelapse mortality in patients with a mismatched related or matched unrelated donor graft. In conclusion, hyperacute GVHD accounts for a substantial proportion of grade II-IV acute GVHD after HSCT. Patients at high risk or with a diagnosis of hyperacute GVHD should be included in clinical studies. (Blood. 2007;

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