Corticosteroids are known to exert antiinflammatory and immunosuppressive effects. Since reactive oxygen species (ROS) induce tissue damage and inflammation and since mononuclear cells (MNCs) generate ROS, we investigated whether corticosteroids inhibit ROS generation by MNCs when given systemically. A single dose of either 300 mg (n = 8) or 100 mg (n = 6) of hydrocortisone (HC) was injected intravenously into eight and six subjects, respectively. Blood samples were obtained before and sequentially after the injection. Following 300 mg HC, N-formylmethionyl leucyl phenylalanine (fMLP)-induced ROS generation, assayed by measuring chemiluminescence with luminol, decreased significantly at 0.5 hours and reached a nadir at 2 hours (8% of basal, P < .001); thereafter, it gradually recovered, but was still below baseline at 24 hours. Following the dose of 100 mg HC, ROS generation decreased significantly at 1 hour (nadir, 30% of basal; P < .01) and gradually recovered to near basal level at 8 hours. Serum cortisol concentrations were markedly elevated over basal and remained elevated throughout the first 8 hours of the experiment, returning to baseline at 24 hours. This inhibition of ROS generation by HC (and other glucocorticoids) may have a role to play in mediating the antiinflammatory action of corticosteroids.