Several different groups have independently demonstrated that non-allospecific memory T cells do not induce GVHD. The data related to the ability of allospecific memory T cells to induce GVHD have not been conclusive. In order to study this question more definitely, we have developed a novel GVHD model using TEa TCR transgenic mice as donors. TEa CD4+ TCR transgenic mice (C57BL/6 background) express a TCR that recognizes the peptide ASFEAQGLANIAVDKA in the context of I-Ab. This peptide corresponds to positions 52–68 from the alpha-chain of I-E class II molecules and is expressed in all APCs from H-2b/I-E+ strains such as CB6F1 mice. Titration experiment demonstrated that as few as 1 × 105 TEa cells were able to induce lethal GVHD in lethally irradiated CB6F1 recipients, making it an ideal model to study the ability of allospecific memory T cells to induce GVHD. Because sufficient numbers of allospecific memory phenotype T cells could not be obtained from the TEa mice or C57BL/6 CD45.1 mice containing TEa cells after priming, we chose the Rag1-/- model. TEa cells were first parked in Rag1-/- mice and then were immunized with irradiated CB6F1 cells. Eight weeks later, TEa cells were harvested from the spleens and effector memory T cells were obtained after depletion of CD62L+ cells. Many TEa cells that were parked in the Rag1-/- mice but were not immunized with alloantigens also obtained the effector memory T cell phenotype. These cells were termed as “unprimed TEM” while those from primed animals were termed as “primed TEM”. Both primed and unprimed effector memory TEa cells were able to respond to alloantigens in vitro. However, neither primed nor unprimed effector memory TEa cells was able to induce lethal GVHD in vivo and all animals in the effector memory T cell groups survived more than 100 days post transplantation. In contrast, all naive T cell recipients developed lethal GVHD and died within 35 days after transplantation. These data demonstrate that, similar to non-allospecific memory T cells, allospecific effector memory T cells also have decreased ability to induce GVHD when compared with naive T cells. This is an excellent model for us to study the unique immune response mediated by allospecific memory T cells in GVHD.