The effects of menopause and hormone replacement therapy (HRT) on the epidermis are largely unknown. The aim of this study was to model and measure the influence of estrogen-transdermal HRT on subtle physiological changes taking place in the epidermis during the perimenopause. Skin capacitance and transepidermal water loss were measured both on normal-looking skin and at the site of a plastic occlusion stress test (POST). Two groups of 15 menopausal women were enrolled. One group was untreated and the other received transdermal estrogen. The water-holding capacity of the stratum corneum was significantly increased at the POST site in women receiving transdermal estrogen. The improvement in the skin water-holding capacity, which is known to be associated with a beneficial effect on the skin barrier function, may contribute to the prevention of several dermatoses.