Hydrocortisone (HC-A) inhibited the proliferative response in the autologous mixed lymphocyte reaction (AMLR). The inhibitory activity became apparent 48 h after initiation of the cultures and was maintained throughout the culture period. T cells from cultures treated with HC-A showed a proliferative response to interleukin-2 (IL-2) of a similar degree as T cells from cultures not exposed to this drug. Hydrocortisone abrogated the production of IL-2 in AMLR. The addition of interleukin-1 (IL-1) to HC-A-treated cultures did not restore or increase the synthesis of IL-2, whereas IL-1 added to non HC-A-treated cultures significantly enhanced the synthesis of IL-2. Finally, IL-2 but not IL-1 could overcome the abrogatory effect of hydrocortisone on proliferation of T cells induced by AMLR. These results indicate that HC-A inhibits proliferation of T cells in AMLR by causing the IL-2 producer T cells to become unresponsive to IL-1 and unable to synthesize IL-2. This drug does not, however, interfere with the process by which resting T cells acquire responsiveness to IL-2.