Previous work has shown that glucocorticoids accelerate splenic T-cell proliferation in vitro. To test whether chronic exposure to high levels of glucocorticoids in vivo would affect this accelerating effect, we offered adrenalectomized rats a high dose of corticosterone (CORT; 150 µg/ml in saline), a physiological replacement dose of CORT (15 µg/ml in saline), or saline to drink. We also included a group of sham-adrenalectomized rats. After one week of treatment, splenic lymphocytes of these animals were cultured in the presence or the absence of 1000 nM CORT. The central finding was that the CORT-evoked acceleration of the proliferative response in vitro was attenuated in splenic T-cells from animals that had received the high-dose CORT treatment in vivo. This observation could not be explained by changes in interleukin 2 (IL-2) levels in culture supernatants, the cellular composition of the spleens, or an altered GR expression in T-cells. As a candidate mechanism, we identified the abrogation of a CORT-evoked enhancement of IL-2 receptor expression. This finding underscores the pivotal role of the IL-2 receptor in the modulation of cellular immunity by glucocorticoids. We conclude that the attenuated acceleration of T-cell proliferation after long-term exposure to elevated glucocorticoid levels may underlie the well-known impairment of immune function under chronic stress.