To characterize the immunological effects of intermittent IL‐2 therapy, which leads to selective increases in CD4⁺ T lymphocytes in HIV‐infected patients, 11 patients underwent extensive immunological evaluation. While IL‐2 induced changes in both CD4⁺ and CD8⁺ cell number acutely, only CD4⁺ cells showed sustained increases following discontinuation of IL‐2. Transient increases in expression of the activation markers CD38 and HLA‐DR were seen on both CD4⁺ and CD8⁺ cells, but CD25 (α chain of the IL‐2 receptor) increased exclusively on CD4⁺ cells. This increase in CD25 expression was sustained for months following discontinuation of IL‐2, and was seen in naive as well as memory cells. IL‐2 induced cell proliferation, but tachyphylaxis to these proliferative effects developed after 1 week despite continued IL‐2 administration. It thus appears that sustained CD25 expression selectively on CD4⁺ cells is a critical component of the immunological response to IL‐2, and that intermittent administration of IL‐2 is necessary to overcome the tachyphylaxis to IL‐2‐induced proliferation.