Graft‐versus‐host disease (GvHD) is a major complication of allogeneic bone marrow transplantation and occurs when donor T cells react with histo‐incompatible recipient's antigens. In thepresent study, we analyzed the contribution of CD4 T cell subsets, defined according to their CD45RC expression level, in the development of acute and chronic GvHD. For this purpose, we used the model of GvHD induced in rats when parental lymphocytes are transferred to irradiated (LEW×BN) F1 hybrid recipients. We showed that parental CD45RC^high (naive cells) CD4 T cells induced both acute and chronic GvHD while CD45RC^low (memory cells) subset did not. In vitro, only CD45RC^high CD4 T cells proliferated and produced cytokines in response to alloantigen stimulation. LEW and BN CD45RC^high CD4 T cells produced different cytokine profiles in response to in vitro allostimulation, which could explain their ability to induce different forms of GvHD. Finally, we showed that memory CD45RC^low CD4 T cells, known to contain regulatory T cells, were unable to prevent GvHD induction. Together these data show that memory CD45RC^low CD4 T cells do not contain functional alloreactive T cells and suggest that selective transfusion of donor memory cells could greatly improve post‐transplant immune reconstitution without riskof GvHD induction.