Objective: To review the effects of non-oral administration of postmenopausal hormone therapy (HT) on risk markers for atherosclerotic and venous thromboembolic disease.Non-oral postmenopausal HT appears not to increase venous thromboembolic risk, whereas the effect on coronary heart disease risk is less clear. Design: Systematic review of literature obtained from MEDLINE, EMBASE, and CENTRAL databases from 1980 until and including April 2006. Terms for "postmenopausal hormone therapy" and for "non-oral administration" were combined in the search. Setting: Randomized clinical trials. Patient(s): Postmenopausal women, both healthy and with established cardiovascular disease or specified cardiovascular risk factors. Intervention(s): Non-oral HT (e.g., transdermal or intranasal) compared with oral HT or no treatment/placebo. Main Outcome Measure(s): Lipoprotein(a), homocysteine, C-reactive protein (CRP), cell adhesion molecules, markers of endothelial dysfunction, coagulation, and fibrinolysis. Result(s): Seventy-two studies investigating either transdermal or intranasal administration were included. For non-oral HT, decreases in lipoprotein(a), cell adhesion molecules, and factor VII generally were significant, resistance to activated protein C (APCr) was slightly increased, and other markers including CRP and homocysteine did not change. Compared with oral HT, changes in CRP and APCr were smaller, changes in cell adhesion molecules and some fibrinolytic parameters tended to be smaller, whereas changes in other factors including lipoprotein(a) and homocysteine did not differ. Conclusion(s): Potentially unfavorable changes seen with oral HT on two important markers, CRP and APCr, are substantially smaller with non-oral HT. Non-oral HT has minor effects on the other cardiovascular risk markers studied. Therefore, compared with oral HT, non-oral HT appears be safer with respect to atherosclerotic and venous thromboembolic disease risk. © 2008 American Society for Reproductive Medicine.