To investigate the role of histone deacetylase3(HDAC3) in T cell homeostasis, we deleted hdac3 in CD4⁺CD8⁺ double positive(DP) stage of thymocytes using the cd4-cre transgene .The CD4Cre-mediated hdac3 deletion did not impact T cell development in the thymus but resulted in a dramatic loss of peripheral T cells. In addition, peripheral T cells in hdac3 knock-out mice showed a dominant activation/effector/memory phenotype. Mechanism analysis revealed an increased cell apoptosis which was accompanied by an accelerated cell proliferation in the peripheral T cells of hdac3 knock-out mice. Moreover, Fas and FasL positive cells and FasL expression increased significantly in the peripheral T cells of hdac3 knock-out mice. In vitro TCR activation did not affect the apoptosis of normal peripheral T cells, but dramatically increased apoptosis of peripheral T cells from hdac3 knock-out mice. Our results presented here indicate an important role of HDAC3 in maintaining homeostasis of peripheral T cells by refraining them from activation- induced cell death.