During the history, the hormone replacement therapy ( HRT) went through different phases, balancing with doses, various forms of application and duration of therapy, all in purpose to decrease the risks of the HRT. The aim of many discussions and studies is to give answers about efficiency and safety of transdermal HRT compared with oral use. Large number of studies proved the same efficacy of estrogen transdermal therapy in reducing vas-omotor symptoms in comparison to oral estrogen therapy, which is the most common indication for usage of HRT in postmenopausal woman. On the other hand, the safety profile of transdermal use of HRT is significantly better due to lower therapeutic doses and by avoiding first pass metabolism. It has been shown that transdermal hormone therapy may have pronounced effect on hepatic pro-tein synthesis such as lipoproteins, an important predictor for myocardial infraction and cardiovas-cular mortality in healthy women. The favorable metabolic profile of transdermal use is apparent through lower incidence of metabolic syndrome and weight gain in comparison to an oral use of HRT. Unlike the oral HRT, the transdermal pathway has no negative affects on the coagulation fac-tors of coagulation, thereby redacts us risk of cerebrovascular insult and thromboembolism in com-parison to oral route of administration, independent of body mass index (BMI). Since the first pass is avoided, the transdermal estrogen administration may have less pronounced negative effect in postmenopausal women with gallbladder disease and gastrointestinal dysfunction, those with meta-bolic syndrome and diabetes type II and those with arterial hypertension and elevated risk of cardi-ovascular disease and deep vein thrombosis. Patients who prefer non- oral use of hormones are can-didates for transdermal estrogen therapy. Tobacco smokers are recommended this route of admin-istration of estrogen since they are at greater risk of cardiovascular incidence. The candidates for transdermal estrogen therapy could be also for patients who have sexual disfunction, migraines and depression. Although there are no data of decreasing the risk for some carcinomas, especially for breast cancer, few studies demonstrate significantly lower risk in comparison to oral route of ad-ministration.