The aim of this study was to investigate the specific role of endogenous glucocorticoids (GC) following restraint stress on thymic involution and apoptosis. Restraint stress has been reported to alter physiological and behavioral responses in experimental animals. Exposure of mice to restraint stress led to involution of the thymus, to a decrease of the CD4+ 8+ thymocyte subset, and to fragmentation of thymic DNA. The role of endogenous GC in restraint stress-induced changes in the thymus was studied by three experimental approaches: surgical adrenalectomy, chemical adrenalectomy, and blocking of GC receptors by a specific type II receptor antagonist. In surgically-Adx mice, which lack endogenous GC, the effects of restraint on the thymus were wholly abrogated. Pretreatment of restrained mice with metyrapone (an 11beta hydroxylase inhibitor that specifically inhibits GC biosynthesis) had the same consequence, and blockage of GC receptors with the specific GC type II receptor antagonist RU-38486 attenuated the effects of the stressor. These findings indicate that GC are involved in the restraint-induced effects on the thymus.