Acute thymic involution is known to be induced under conditions of physical stress, bacterial infections, and malignancies. It is speculated that glucocorticoids, tumor necrosis factor (TNF), and other factors may act as mediators for the thymic involution under such conditions. It was herein investigated whether either lymphotoxin (TNF beta) or estrogen could induce thymic involution without the help of glucocorticoids. Interestingly, both lymphotoxin or estrogen alone induced profound thymic involution even in adrenalectomized mice. In contrast to glucocorticoids, which induce lymphocytopenia throughout the organs, lymphotoxin and estrogen did not induce lymphocytopenia in the peripheral organs. More importantly, lymphotoxin and estrogen rather stimulated extrathymic T cells in the liver and other organs. These results suggest that lymphotoxin and estrogen per se might be important regulators of immune systems.