To investigate the influence of estrogen replacement on serotonergic activity in postmenopausal women, the serotonin agonist meta-chlorophenylpiperazine (m-CPP) (0.5 mg/kg) was given orally to 18 normal postmenopausal women, 11 of whom were also tested following 30 days' treatment with estrogen transdermal patches (estraderm 0.1 mg). Fifteen normal, healthy women of reproductive status served as a control group. Cortisol and prolactin responses to m-CPP were measured. Without estrogen, the prolactin and cortisol responses of postmenopausal women to m-CPP were blunted compared to those of reproductive women. Estrogen replacement increased the hormonal responses. It is suggested that decreased serotonergic activity in postmenopausal women might contribute to their vulnerability to affective disorders. Estrogen replacement therapy might decrease this vulnerability and might add to the efficacy of serotonergic antidepressants when warranted.