Treatment of adult intact rats with sex steroids (estradiol-17 beta, ethynylestradiol, dihydrotestosterone) raises the concentration of serum acute-phase alpha 1-acid glycoprotein (AGP). Estrogens are more effective than dexamethasone, and experimental inflammation causes an additive effect on AGP synthesis when ethynylestradiol is given simultaneously. Adrenaline is also able to increase the AGP level. Experiments with adrenalectomized and adrenalectomized plus castrated rats result in a 50% reduction in the serum level of AGP as compared with that in normal and hypophysectomized rats. Although ethynylestradiol is the strongest inducer of AGP synthesis in intact animals, it is unable to enhance significantly the AGP level in adrenalectomized rats, contrary to dexamethasone. Adrenalectomized rats are incapable of undergoing a substantial increase in plasma AGP level following experimental inflammation, and ethynylestradiol or adrenaline cannot take the place of dexamethasone in inducing high levels of AGP in these inflamed rats. These results indicate that glucocorticoids play an obligatory role in modulating AGP synthesis either by directly regulating the AGP gene or in modulating AGP synthesis by increasing the stability of AGP mRNA. Finally, it is suggested that glucocorticoids may also act in unmasking receptor binding sites at the AGP gene level for other mediators such as sex steroids and putative inflammatory factors.