Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention. A total of 27,347 postmenopausal women aged 50–79 years were enrolled at 40 US centers to the Women’s Health Initiative trial . Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/day) plus medroxyprogesterone acetate (MPA; 2.5 mg/day) ([i]n[/i] = 8506) or placebo ([i]n[/i] = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/day) ([i]n[/i] = 5310) or placebo ([i]n[/i] = 5429). The intervention lasted a median of 5.6 years in CEE + MPA trial and 7.2 years in the CEE-alone trial with 13 years of cumulative follow-up until September 30, 2010. During the CEE + MPA intervention phase, the numbers of coronary heart disease (CHD) cases were 196 for CEE + MPA vs. 159 for placebo (hazard ratio (HR) 1.18; 95% confidence interval (CI) 0.95–1.45) and 206 vs. 155, respectively, for invasive breast cancer (HR 1.24; 95% CI 1.01–1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged ≥ 65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated post-intervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE + MPA vs. 323 for placebo; HR 1.28; 95% CI 1.11–1.48). The risks and benefits were more balanced during the CEE-alone intervention with 204 CHD cases for CEE-alone vs. 222 cases for placebo (HR 0.94; 95% CI 0.78–1.14) and 104 vs. 135, respectively, for invasive breast cancer (HR 0.79; 95% CI 0.61–1.02); cumulatively, there were 168 vs. 216, respectively, cases of breast cancer diagnosed (HR 0.79; 95% CI 0.65–0.97). Results for other outcomes were similar to CEE + MPA. Neither regimen affected all-cause mortality. For CEE-alone, younger women (aged 50–59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index. Absolute risks of adverse events (measured by the global index) per 10,000 women annually taking CEE + MPA ranged from 12 excess cases for ages of 50–59 years to 38 for ages of 70–79 years; for women taking CEE-alone, from 19 fewer cases for ages of 50–59 years to 51 excess cases for ages of 70–79 years. Quality-of-life outcomes had mixed results in both trials. In conclusion, findings from the intervention and extended post-intervention follow-up of the two WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women.