Background: While praised for its benefits in treating symptoms related to menopausal changes, hormone replacement therapy (HRT) has been associated with an increased risk for hormone-dependent cancer development, particularly endometrial and breast. Few studies have elucidated the relationship between HRT cessation and hormone receptor-positive breast cancer proliferation. We report herein, to the best of our knowledge, the first case of 28.6% relative reduction in proliferation index marker Ki-67 in nodepositive hormone receptor-positive breast cancer following HRT cessation.Case Description: We report an unusual case of a 64-year-old female patient with longstanding HRT for fifteen years who underwent immediate discontinuation after diagnosis of poorly differentiated invasive ductal carcinoma. We observed a reduction in tumor grade from poorly differentiated at time of biopsy to moderately differentiated at time of surgery following cessation of HRT, as well as a reduction in the tumor proliferation index (Ki-67) from 70% to 50%. The patient has remained recurrence-free at the one-year mark postoperatively with continued follow-up.Conclusions: This case highlights potential clinical benefits associated with HRT discontinuation in the postmenopausal population with preexisting hormone-dependent cancers with high proliferation index, as well as the usefulness of Ki-67 in measuring response to aromatase inhibition in this subpopulation of patients.