Estrogen replacement therapy is widely used in postmenopausal women. The current study examines the effect of varying concentrations of estrogen on the levels of activity of monoamine oxidase A and -B in brain and in other tissues. Adult female rats were ovariectomized and randomized to receive a subcutaneous, slow-release preparation of either placebo or one of three doses of 17-beta-estradiol (0.05, 0.5, or 5.0 mg/pellet, estimated serum levels of 20-25 pg/ml, 100-600 pg/ml, and 1-2 ng/ml, respectively). Animals were sacrificed at 3 weeks and MAO-A and -B activity was assessed in homogenates of heart, liver, lung, uterus, kidney, adrenal and small intestine using 5-hydroxytryptamine and phenylethylamine as substrates. Cortex, amygdala and hypothalamus were microdissected from frozen sections of the brain and were also assayed for MAO-A and -B activity. High dose estrogen (5 mg/pellet) significantly decreased MAO-B activity and resulted in lesser or insignificant changes in MAO-A activity, respectively in liver (-30%, +1%), kidney (-22%, -11%), and uterus (-57%, -35%) (p < 0.05). No significant changes in enzyme activity were observed in heart, adrenal, lung and small intestine. In brain, estrogen (5 mg/pellet) decreased MAO-A activity in the hypothalamus (-28%) and amygdala (-21%), with no significant change seen in MAO-B. Our results suggest that estrogen exerts a tissue-specific, differential regulation of MAO-A and -B activity.