We investigated in this study the effect of a synthetic glucocorticoid hormone, dexamethasone (Dex), on apoptosis of human peripheral blood neutrophils. Dex inhibited spontaneous and tumor necrosis factor-alpha (TNF-alpha)-induced neutrophil apoptosis in a concentration- and time-dependent manner. This effect of Dex on neutrophil apoptosis was completely reversed by a glucocorticoid receptor antagonist, RU38486, and by cycloheximide. The decrease in sensitivity to TNF-alpha-induced apoptosis cannot be ascribed to a down-modulation of TNF receptors on these cells. These observations suggest that a glucocorticoid hormone participates in the regulation of neutrophil apoptosis and that inhibition of human neutrophil apoptosis by Dex is mediated through glucocorticoid-receptor-induced de novo synthesis of macromolecules. Possible mechanisms and implications of this phenomenon are discussed.