A dministration of IL-2 to HIV-infected patients leads to expansion of a unique subset of CD4⁺CD45RO^–CD25⁺ cells. In this study, the origin, clonality, and function of these cells were investigated. Analysis of TCR excision circles revealed that the CD4⁺CD45RO^–CD25⁺ cells were the product of peripheral expansion but remained polyclonal as determined by TCR repertoire analysis. Phenotypically, these cells were distinct from naturally occurring Tregs; they exhibited intermediate features, between those of memory and naive cells, and had lower susceptibility to apoptosis than CD45RO^–CD25^– or memory T cells. Studies of intracellular cytokine production and proliferation revealed that cytokine-expanded naive CD25⁺ cells had low IL-2 production and required costimulation for proliferation. Despite elevated expression of forkhead transcription factor P3 (foxP3), they exerted only weak suppression compared with CD45RO⁺CD25^+high cells (Tregs). In summary, in vivo IL-2 administration to HIV-infected patients leads to peripheral expansion of a population of long-lived CD4⁺CD45RO^–CD25⁺ cells that express high levels of foxP3 but exert weak suppressive function. These CD4⁺CD25⁺ cytokine-expanded naive cells, distinct from antigen-triggered cells and Tregs, play a role in the maintenance of a state of low turnover and sustained expansion of the CD4⁺ T cell pool.