It has been recently shown (Seddiki, N., B. Santner-Nanan, J. Martinson, J. Zaunders, S. Sasson, A. Landay, M. Solomon, W. Selby, S.I. Alexander, R. Nanan, et al. 2006. J. Exp. Med. 203:1693–1700.) that the expression of interleukin (IL) 7 receptor (R) α discriminates between two distinct CD4 T cell populations, both characterized by the expression of CD25, i.e. CD4 regulatory T (T reg) cells and activated CD4 T cells. T reg cells express low levels of IL-7Rα, whereas activated CD4 T cells are characterized by the expression of IL-7Rα^high. We have investigated the distribution of these two CD4 T cell populations in 36 subjects after liver and kidney transplantation and in 45 healthy subjects. According to a previous study (Demirkiran, A., A. Kok, J. Kwekkeboom, H.J. Metselaar, H.W. Tilanus, and L.J. van der Laan. 2005. Transplant. Proc. 37:1194–1196.), we observed that the T reg CD25⁺CD45RO⁺IL-7Rα^low cell population was reduced in transplant recipients (P < 0.00001). Interestingly, the CD4⁺CD25⁺CD45RO⁺IL-7Rα^high cell population was significantly increased in stable transplant recipients compared with healthy subjects (P < 0.00001), and the expansion of this cell population was even greater in patients with documented humoral chronic rejection compared with stable transplant recipients (P < 0.0001). The expanded CD4⁺CD25⁺CD45RO⁺IL-7Rα^high cell population contained allospecific CD4 T cells and secreted effector cytokines such as tumor necrosis factor α and interferon γ, thus potentially contributing to the mechanisms of chronic rejection. More importantly, CD4⁺IL-7Rα⁺and CD25⁺IL-7Rα⁺ cells were part of the T cell population infiltrating the allograft of patients with a documented diagnosis of chronic humoral rejection. These results indicate that the CD4⁺CD25⁺IL-7Rα⁺ cell population may represent a valuable, sensitive, and specific marker to monitor allospecific CD4 T cell responses both in blood and in tissues after organ transplantation.