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To determine the risk-benefit ratio of hormone replacement therapy (HRT) and the cost-effectiveness of screening in perimenopausal and postmenopausal women who are carriers of factor V Leiden, as well as to provide evidence-based clinical recommendations for the primary care provider.Databases searched included EMBASE, BIOSIS, MEDLINE, CINAHL, PubMed, SciSearch, and the Cochrane Database. Two reviewers extracted, reviewed, and concurred upon relevant evidence identified in the data-bases.Results confirmed that all women have a higher risk for the development of venous thrombosis while on HRT. The presence of a genetic mutation, such as factor V Leiden, in combination with HRT dramatically increased an individual's chance for developing venous thrombi.Based on the findings of the studies reviewed, it is recommended that women wishing to initiate HRT be thoroughly screened for known risk factors of thrombosis. If risk factors are identified, genetic testing for factor V Leiden may be warranted.