To evaluate the potential role of serotonin in the premenstrual syndrome (PMS), we investigated the effects of menstrual cycle phase on neuroendocrine and behavioral responses to the serotonergic agent m-chlorophenylpiperazine (m-CPP) in women with PMS and controls. A single oral dose of m-CPP (0.5 mg/kg) was administered to 10 PMS patients and 10 healthy controls during the follicular and luteal phases of the menstrual cycle. We observed the following. m-CPP administration during the luteal phase resulted in an acute improvement of PMS symptoms; the plasma cortisol and ACTH responses to m-CPP were blunted in both menstrual cycle phases in PMS patients compared with controls. These data provide evidence for the acute efficacy of m-CPP in the treatment of PMS. Although there is additional evidence for dysregulation of either the hypothalamic-pituitary-adrenal axis or serotonin control of the hypothalamic-pituitary-adrenal axis in women with PMS, there is little evidence for luteal phase-specific serotonergic dysfunction. These findings, nonetheless, implicate the serotonin system as a modulating (not causal) factor in PMS.