The complications of hormone replacement therapy (HRT) related to hypercoagulability are well known. However, there have been no cases of prosthetic valve thrombosis reported in the literature in conjunction with HRT. The present report discusses a case of acute mitral prosthetic valve thrombosis associated with the initiation of HRT. Because hypercoagulability is usually associated with significant morbidity and mortality, caution should be exercised in the management of patients with prosthetic valve thrombosis receiving HRT.