Administration of exogenous interleukin-18 (IL-18) regulates experimental acute graft-versus-host disease (GVHD) in a Fas-dependent manner when donor CD4⁺ T cells are required for mortality after experimental allogeneic bone marrow transplantation (BMT). However, CD4⁺ and CD8⁺ T cells can induce acute GVHD after clinical allogeneic BMT, and the role of IL-18 in CD8⁺-mediated acute GVHD is unknown. We, therefore, determined the role of IL-18 in GVHD mediated by CD4⁺ or CD8⁺ T cells across major histocompatibility complex (MHC) class II- and class I-disparate allogeneic BMT, respectively. Administering IL-18 significantly increased survival in CD4⁺-mediated GVHD but reduced survival in CD8⁺-mediated GVHD. This increase in deaths was associated with significantly greater clinical, biochemical, and histopathologic parameters of GVHD damage and was independent of Fas expression on donor T cells. Administering IL-18 significantly enhanced allospecific cytotoxic function and expansion of CD8⁺ cells. Endogenous IL-18 was critical to GVHD mediated by CD8⁺ donor T cells because IL-18 receptor-deficient donors caused significantly less GVHD but exacerbated CD4⁺-mediated, GVHD-related death. Furthermore, administering anti-IL-18 monoclonal antibody significantly reduced CD8⁺-mediated, GVHD-related death. Together these findings demonstrate that IL-18 has paradoxical effects on CD4⁺ and CD8⁺ cell-mediated GVHD. (Blood. 2004;104:3393-3399)