Glycyrrhetinic acid (GA) is known to inhibit glucocorticoid metabolism inhibiting 11beta-hydroxysteroid dehydrogenase (11beta-HSD). Moreover, GA administration to mice has been shown to affect the lymphoid organs through elevation of endogenous corticosterone concentration. The effect of GA administration on thymus has been demonstrated to show that considerable amounts of thymocytes undergo apoptosis by elevated levels of corticosterone in systemic circulation. However, the effect of GA administration on peripheral lymphocytes has remained unknown. In our current study, we demonstrated that a significant involution of spleen as well as thymus occurred within 24 h of a single administration of GA in mice. In addition, a flow cytometric analysis of the splenocytes taken from mice treated with GA showed a significant increase in the number of apoptotic cells which exhibited translocated phosphatidylserine outside the plasma membrane. Furthermore, considerable inhibition of 11beta-HSD activity in GA-treated mice was observed in liver and spleen, resulting in a significant increase in concentration of corticosterone in the blood. These facts showed that the apoptosis of splenocytes was the result of indirect effect of GA through elevated levels of corticosterone. We confirmed this using cultured splenocytes in vitro where no apoptotic effect of GA was observed. We concluded that GA administration induces cell death of not only thymocytes that are naive to corticosterone, but also splenocytes that are usually stable to its physiological concentrations.