A few previous reports have suggested that megestrol acetate, a synthetic progestational agent frequently used as an antineoplastic drug, suppresses serum cortisol concentrations in humans. To explore this concept further, we prospectively performed several measurements of the pituitary-adrenal axis in patients receiving megestrol acetate (160 or 800 mg/day). The data from these evaluations demonstrate that megestrol acetate reversibly decreases serum cortisol concentrations in humans and that this effect seems to originate from a suppression of the pituitary-adrenal axis. Additional studies should be conducted to determine the implications of the low levels of serum cortisol.