The results from the present study demonstrate that the innate defense mechanisms which control the progressive growth of Listeria monocytogenes in normal animals in vivo are dependent upon the active catabolism of endogenous glucocorticoids by the enzyme 11b-hydroxysteroid dehydrogenase (11b-HSD). When 11b-HSD activity was pharmacologically inhibited in vivo, host susceptibility to progressive bacterial disease was markedly increased. Depressed natural resistance following 11b-HSD inhibition correlated with changes in the patterns of inducible cytokines by macrophages and T cells. Similar changes were observed when normal adult animals were treated with low doses of dexamethasone prior to experimental infection with Listeria.