There may be episodes of vaginal spotting and acyclic bleeding in postmenopausal women receiving continuous combined hormone replacement therapy (HRT). The pathogenesis of this irregular bleeding is so far unclear. Most investigations deal with the pathophysiology of these processes in young women taking combined oral contraceptive pills. However, contraceptive use and a continuous HRT regimen are not the same. The possible mechanisms of bleeding during HRT may include a change in the ratio of pro- and antiangiogenic factors - vascular endothelial growth factor and thrombospondin-1, impairments of metalloproteinases and their tissue inhibitors, changes in tissue factor - a mediator of endometrial hemostasis, and an increase in endometrial leukocyte counts with natural killer-cell predominance. Each of the above factors is the subject of in vivo and in vitro studies since an unclear relationship has been found between these hypotheses and the occurrence of bleeding during continuous combined HRT. Unfortunately, therapeutic methods for correcting this complication are lacking now. It is important to monitor patients in order to rule out endometrial neoplastic processes.