This chapter describes some prophylactic trials concerned with hormone replacement therapy. It first discusses the postmenopausal estrogen/progestin interventions trial (PEPI), which provides much useful information for women trying to decide whether to use hormone replacement therapy and which regimen to use. The chapter then describes the Women's Health Initiative of long-term effects of a low-fat dietary pattern, hormone replacement therapy, and calcium/vitamin D supplements on the incidence of several diseases, and the Heart Estrogen/progestin Replacement Study (HERS) to prevent recurrence of coronary heart disease. Overall goals of the Women's Health Initiative are to test means of reducing the risk for cardiovascular disease, breast cancer, colorectal cancer, and osteoporotic fractures in women. Finally, the chapter briefly mentions the Nurses' Health Study, which although not a randomized trial, has provided an enormous amount of information on risk factors for diseases in women.