Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic stem cell transplantation. Effector memory T cells (TEM)do not cause GVHD but engraft and mount immune responses, including graft-versus-tumor effects. One potential explanation for the inability of T EM to cause GVHD is that T EM lack CD62L and CCR7, which are instrumental in directing naive T cells (T N) to lymph nodes (LN) and Peyer patches (PP), putative sites of GVHD initiation. Thus T EM should be relatively excluded from LN and PP, possibly explaining their inability to cause GVHD. We tested this hypothesis using T cells deficient in CD62L or CCR7, transplant recipients lacking PNAd ligands for CD62L, and recipients without LN and PP or LN, PP, and spleen. Surprisingly, CD62L and CCR7 were not required for T N-mediated GVHD. Moreover, in multiple strain pairings, GVHD developed in recipients that lacked LN and PP. Mild GVHD could even be induced in mice lacking all major secondary lymphoid tissues (SLT). Conversely, enforced constitutive expression of CD62L on T EM did not endow them with the ability to cause GVHD. Taken together, these data argue against the hypothesis that T EM fail to induce GVHD because of inefficient trafficking to LN and PP.