The Women's Health Initiative (WHI) was a placebo-controlled randomized study that investigated the benefits and risks of 2 menopausal hormone regimens in healthy normal postmenopausal women. The present report provides a comprehensive, integrated overview of findings from the intervention and extended postintervention phases of 2 WHI trials: one used conjugated equine estrogens (CEEs) plus medroxyprogesterone acetate (MPA), and the other used CEEs alone.Between 1993 and 1998, 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. Women with an intact uterus were randomized to receive a regimen of CEEs (0.625 mg/d) plus MPA (2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy were randomized to receive CEEs alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention phase of the CEEs plus MPA trial lasted a median of 5.6 years, and that of the CEEs alone trial lasted a median of 7.2 years with 13 years of cumulative follow-up until September 30, 2010. Primary efficacy and safety outcomes for both trials were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index of other health outcomes included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death.Benefits in the CEEs plus MPA intervention phase included decreased hip fractures, diabetes, and vasomotor symptoms. During the intervention phase in the CEEs plus MPA group, there were 196 CHD cases versus 159 for placebo (hazard ratio [HR], 1.18; 95% confidence interval [CI], 0.95-1.45), and 206 invasive breast cancer cases versus 155 for placebo (HR, 1.24; 95% CI, 1.01-1.53). Moreover, risks increased for stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence. Among women in the CEEs plus MPA group, most risks and benefits dissipated after intervention, but there was persisting elevation in risk of breast cancer (434 cases vs 323 for placebo; HR, 1.28; 95% CI, 1.11-1.48).During the intervention phase in the CEEs alone group, risks and benefits were more balanced; there were 204 CHD cases versus 222 cases for placebo (HR, 0.94; 95% CI, 0.78-1.14) and 104 cases of invasive breast cancer compared with 135 for placebo (HR, 0.79; 95% CI, 0.61-1.02). Moreover, during cumulative follow-up, 168 cases of breast cancer were diagnosed in the CEEs alone group compared with 216 for the placebo; the HR was 0.79, with a 95% CI of 0.65 to 0.97. Other outcomes in this group were similar to the CEEs plus MPA group. All-cause mortality was not affected with either regimen. Younger women (aged 50-59 years) in the CEEs alone group had more favorable results during the intervention phase than older women for all-cause mortality, myocardial infarction, and the global index.Compared with placebo, absolute risks of adverse events in the CEEs plus MPA group assessed using global index data were lower in younger women: women aged 50 to 69 years had 12 more adverse events per 10,000 person-years, whereas those aged 70 to 79 years had 38 more. In the CEEs alone group, women aged 50 to 59 years had 19 fewer adverse events per 10,000 person-years, and women aged 70 to 79 years had 51 more adverse events. In both trials, results of quality-of-life outcomes were mixed.These findings do not support the use of CEEs plus MPA or CEEs alone in postmenopausal women for prevention of chronic disease. However, hormonal treatment may be beneficial in generally healthy women during early menopause for management of moderate to severe menopausal symptoms. © 2014 by Lippincott Williams & Wilkins.