We studied whether allospecific CD4⁺ effector memory T cells (T_EM) could induce graft-versus-host disease (GVHD) using a novel GVHD model induced solely by CD4⁺ T cell receptor transgenic TEa cells. Allospecific T_EM generated in a lymphopenic host bore a typical memory phenotype. Moreover, these cells were able to elicit a faster and more effective proliferative response on challenge with alloantigen in vitro and to mediate “second-set” skin graft rejection in vivo. However, these allospecific T_EM were unable to induce GVHD. Allospecific T_EM recipients became tolerant to alloantigen as a result of clonal deletion. Even though allospecific T_EM were able to respond to alloantigen initially, the expansion of these cells and inflammatory cytokine production during GVHD were dramatically decreased. The inability of allospecific T_EM to sustain the alloresponse may be a result of enhanced activation-induced cell death. These observations provide insight into how allospecific CD4⁺ T_EM respond to alloantigen during GVHD and underscore the fundamental differences in alloresponses mediated by allospecific T_EM in graft rejection and GVHD settings.