In 1991, the U.S. National Institutes of Health (NIH) launched the biggest clinical trial of all time to evaluate important risk factors for multiple disease endpoints in women, the Women's Health Initiative (WHI). The randomized clinical trial of hormone-replacement therapy, vitamin D, calcium, and other risk factors and exposures in about 50,000 women was accompanied by an observational study of 160,000 women. Breast cancer, endometrial cancer, cardiovascular disease, and osteoporosis were among the multiple endpoints. Findings for hormone replacement therapy were particularly surprising and led to major changes in practice by physicians and patients worldwide. Important new findings continue to be released. The latest information suggests that the trial's results may have influenced the prevention of heart disease, but not stroke. The importance of long-term follow-up of randomized prevention trials is well demonstrated by the emergence of new findings showing very different long-term effects and different effects by age from estrogen alone versus estrogen plus progesterone. These findings are a model for comparative effectiveness research. Long-term results from dietary modification and calcium and vitamin D supplements are being analyzed. Finally, there is debate about the costs and benefits of such large projects. The symposium is dedicated to Dr. Bernadine Healy, the first female director of NIH, who fundamentally changed the medical community's approach to women's health.