Exposure of mice to different types of acute stress (acceleration, ether anesthesia, restraint, overcrowding) or injection of adrenocorticotropic hormone resulted in an increase of plasma corticosteroid levels. This was associated with a decreased immune reactivity of their spleen cells in vitro. In contrast, after repeated exposure to ether stress, no immunosuppression was observed. Pretreatment of cell donors with diazepam prior to acute stress antagonized the immunosuppressive effect of restraint but was ineffective against the consequences of ether anesthesia. On the other hand, desipramine did not interfere with either type of stress response. Unresponsive spleen cell cultures could be reactivated by adding macrophages and B cells from normal mice. Addition of macrophages, B or T cells alone, or combinations of T cells with macrophages or B cells, had no restorative effect. Restraint stress significantly increased the homing of 51Cr-labeled lymph node cells from normal nu/+ mice (B and T cells) to spleen and bone marrow. In contrast, homing of nu/nu lymph node cells (B cells) to lymph nodes and spleen was decreased in stressed recipients, and an increased proportion of cells was found in the liver. Hypophysectomy of cell donors resulted in a persistent depression of immune responsiveness, which was restored by treatment with somatotropic hormone (STH). STH presumably accelerates recovery from stress-induced immunosuppression. Moreover, exogenous STH interfered with the effect of increased endogenous corticosterone.