This article presents the case of a 53-yr-old male patient who developed hyperacute lethal graft-vs.-host disease (GVHD) after receiving denileukin diftitox for recurrent peripheral T cell lymphoma after allogeneic hematopoietic stem cell transplantation.In this case, posttreatment skin and colon biopsy specimens exhibited a marked decreased in CD3+ and FOXP3+ T cells compared with pretreatment biopsy specimens, suggesting a role for denileukin diftitox in depleting T regulatory cells, resulting in fulminant GVHD.