The purpose of this review paper is to compare the similarities and differences of oral and transdermal hormone replacement therapy, mainly estrogen, in postmenopause. Hormone replacement therapy is used to prevent and treat menopause-related symptoms such as vasomotor symptoms, vulvovaginal atrophy, and osteoporosis. It consists mostly of estrogens combined with progestins in women who have a uterus, and estrogens in women who have been hysterectomized. Oral hormone replacement therapy, although very effective in the reduction of most menopausal symptoms, is associated with an increased risk of venous thromboembolism, breast carcinoma, coronary heart disease, and stroke. Venous thromboembolism is the most common serious side effect of taking hormone replacement therapy. The increased risk is primarily associated with the liver metabolism of oral estrogens and their first-pass effect on the liver, non-physiological estradiol/estrone ratio in the circulation, and high doses of estrogen due to decreased bioavailability. Low-dose estrogen and different routes of administration, such as the transdermal and vaginal route, have been reasearched in the last two decades due to the mentioned side effects and risks. The vaginal route is used primarily for treating vulvovaginal atrophy. Transdermal therapy has been proven to be as effective as oral therapy in reducing vasomotor symptoms. In the transdermal route of administration, there is a significantly lower liver metabolism and first-pass effect on the liver, and therefore it does not increase the risk of venous thromboembolism, unlike oral therapy. It is possible that transdermal estrogen can be beneficial in regard to other adverse side effects of oral therapy since it maintains a similar physiological serum estradiol/estrone ratio to that found in women of reproductive age. Moreover, its bioavailability is much higher and therefore it can be administered in lower doses. This paper reviews some of the adverse side effects of hormone replacement therapy and how different routes of administration can affect them.