The aim of this study was to determine the effects of the isopropanolic extract of black cohosh (Remifemin) on mammographic breast density and breast epithelial proliferation in healthy, naturally postmenopausal women with climacteric symptoms. This was a prospective, open, uncontrolled drug safety study in which baseline status was compared with status after 6 months of treatment by blinded observers. A total of 74 women were treated with 40 mg black cohosh daily, and 65 women completed the study. Mammograms were performed, and breast cells were collected by percutaneous fine needle aspiration biopsies at baseline and after 6 months. Mammographic density was quantified according to the Wolfe classification or a percentage scale. Breast cell proliferation was assessed using the Ki-67/MIB-1 monoclonal antibody. Safety was monitored by adverse event reporting, laboratory assessments, and measurement of the endometrium by vaginal ultrasound. None of the women showed any increase in mammographic breast density. Furthermore, there was no increase in breast cell proliferation. The mean change +/- SD in proportion of Ki-67-positive cells was -0.5% +/- 2.4% (median, 0.0; 95% CI = -1.32 to 0.34) for paired samples. The mean change in endometrial thickness +/- SD was 0.0 +/- 0.9 mm (median, 0.0). A modest number of adverse events were possibly related to treatment, but none of these were serious. Laboratory findings and vital signs were normal. The findings suggest that the isopropanolic extract of black cohosh does not cause adverse effects on breast tissue. Furthermore, our data do not indicate to any endometrial or general safety concerns during 6 months of treatment.