The endocrine effects of cimetidine (Tagamet) during the menstrual cycle were investigated in seven healthy female volunteers. The subjects were studied for six menstrual cycles divided into the pretreatment phase, a phase of therapy with 1.2 g of orally administered cimetidine daily for two cycles, and a post-treatment phase. Cimetidine therapy induced a significant increase in the mean plasma level of follicle-stimulating hormone during the periovulatory period, followed by modest but sustained hyperprolactinemia throughout the luteal phase of each cycle. No significant changes were found in the mean plasma levels of luteinizing hormone and progesterone, and the mean plasma estradiol level was significantly decreased only in the midproliferative phase of each cycle. The mean plasma prolactin levels after a bolus injection of thyrotropin-releasing hormone in the midluteal phase during cimetidine administration did not differ from the mean control levels, which indicates that cimetidine modulates the release of prolactin at the suprapituitary locus. However, the significance of the endocrine changes remains to be established.