Background. End-stage renal disease (ESRD) is associated with T-cell dysregulation, leading to a variable degree of lymphopenia and increased T-cell differentiation. This may cause a relevant reduction in T-cell immunity, yielding a lowered risk for acute rejection (AR) of kidney allografts. Methods. Before kidney transplantation, circulating CD4(+) and CD8(+) T-cell differentiation was established by determining the frequency of naive T cells, central memory and effector memory T cells, and the highly differentiated CD8(+) Temra cells. In addition, the frequency of differentiated T cells without expression of the costimulatory molecule CD28 was measured. Results. In 47 patients of the 185 patients included, a biopsy-proven AR occurred. Compared with healthy controls, T cells of patients with ESRD were significantly more differentiated. Patients with AR showed the least signs of T-cell dysregulation with significantly more T cells, more naive T cells, and less terminal differentiation of memory T cells compared with nonrejecting patients. After multivariate analysis, only the frequency of terminally differentiated CD8(+) Temra cells (per percent, Conclusions. Advanced ESRD-related T-cell dysregulation that is associated with a relative increase of terminally differentiated CD8(+) Temra cells protects against AR after kidney transplantation.