OX40 (CD134), an activation-induced costimulatory molecule, is mainly expressed on CD4(+) T cells. Several reports, including previous reports from our laboratory, suggest that OX40-mediated signaling plays an important role in the development of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (Allo HSCT). Here, we show that peripheral blood CD4(+)OX40(+) T cells are a unique cell subset as they possess the homing receptors of lymph nodes, and some of them have an exceptional capacity to produce high levels of interleukin-2 (IL-2) upon the stimulation through T cell receptors. Stimulation with IL-7 acts selectively on CD4(+)OX40(+) T cells not only to induce antigen-independent growth but also to increase the frequency of cells with IL-2-producing potential. Simultaneous, but not sequential, ligation of the T cell receptor and OX40 induces CD4(+)OX40(+) T cells to produce far more IL-2, which causes them to proliferate abundantly and differentiate readily into Th1- or Th2-biased effector memory T cells, especially in Allo HSCT recipients. Although not all the CD4(+)OX40(+) T cells had IL-2-producing capacity, Allo HSCT recipients with chronic GVHD (cGVHD) had a significantly higher frequency of IL-2-producing OX40(+) cells in their peripheral blood CD4(+) T cell subset than Allo HSCT recipients without cGVHD. Collectively, CD4(+)OX40(+) T cells with IL-2-producing potential are expected to be privileged for growth and differentiation in lymph nodes upon antigen presentation, suggesting that they might be involved in the process of inducing or maintaining cGVHD.