Various mechanisms for understanding antigenic competition have been proposed, such as macrophage availability, suppressor cells and their soluble products. In view of the regulatory function of some hormones on the immune system, the role of immunosuppressive adrenal corticosteroids in antigenic competition was investigated. When horse red blood cells (HRBC) were injected into rats a five-fold increase in corticosterone blood levels was measured by day 6 and a strong decrease was noted on day 11. In animals injected with HRBC and on day 6 with a second antigen (sheep red blood cells, SRBC), the corticosteroid level was high on day 11. Such high levels are immunosuppressive. To impede such increases in adrenal hormone levels, rats were adrenalectomized. Adrenalectomized or sham-operated animals receiving SRBC only showed no difference in plaque-forming cell (PFC) numbers. All sham-operated rats injected first with HRBC and 5 days later with SRBC showed the expected antigenic competition. Adrenalectomized rats also injected with both antigens sequentially had a five fold increase in number of PFC when compared with the sham-operated controls which had received both antigens. A detailed analysis of these data revealed that a proportion of adrenalectomized animals had PFC numbers within the normal range. In vitro, hydrocortisone enhances the response of spleen cells when only one antigen (SRBC) is present. Prior addition of the unrelated antigen (HRBC) impedes this enhancement. Thus, in a hydrocortisone-enriched culture medium, the presence of the first antigen can interfere with the immune response to the second unrelated antigen, mimicking in vitro a condition of antigenic competition. These findings indicate that hormones may have a role in antigenic competition.