The effectiveness of estrogen therapy for alleviating severe depressions was investigated in a double blind study in which large doses of estrogen were administered to 15 premenopausal and 8 postmenopausal women and placebos were administered to 12 premenopausal and 5 postmenopausal women. The estrogens and placebos were administered over a three month period, and the women were blind rated each week by psychologists and psychiatrists using Hamilton rating scales for depression. There was a significant decline in the depression scores for the group treated with estrogens when compared to the placebo treated group. Considerable variation in the degree of improvement for the women in the estrogen treated group was observed. These variations were not related to age or to menstrual status but were significantly related to depression duration. Women with shorter histories of depression were more likely to show improvement than women with longer illness durations. Efforts were also made to understand the physiological mechanisms through which estrogen treatment contributed toward reducing depression. Previous studies revealed that decreased availability of norepinephrine at the central adrenegic receptor sites in the brain was related to the manifestation of depression while increased availability of norepinephrine at these sites was ralated to a manifestation of elation. Increased availability of norepinephrine has been shown to be related to an inhibition of monoamine oxidase activity (MAO), and estrogen, in turn, has been demonstrated to inhibit MAO activity. During the 3 month study period, 2 blood samples were obtained from the women every week and analyzed for MAO activity. All patients had elevated levels of plasma MAO activity prior to treatment. In estrogen treated patients, MAO levels declined significantly; MAO levels unexplicably increased for the placebo treated group. Reduced MAO activity was not, however, significantly correlated with lower depression ratings. In determining the risk/benefit ratio of estrogen therapy both the risk of developing endometrial cancer and the risks of life long disability and suicide stemming from severe depression should be considered. Tables show 1) mean depression ratings and average MAO activity levels before and after treatment for the estrogen and placebo treated groups and 2) degree of change in depression ratings before and after treatment for both groups of women.