Most researchers are already well aware of recent findings from the Women's Health Initiative regarding the effects of estrogen plus progestin in healthy postmenopausal women.1 The results of this randomized placebo-controlled trial came as a surprise, because many of us assumed that the findings would support estimates obtained from observational cohorts (as well as expert rationale) that suggested that hormone replacement therapy would reduce coronary heart dis? ease and provide an overall benefit to recipients.2,3 The finding from the trial is quite the opposite?after an average of 5.2 years of follow-up of 16,608 women, clinically meaningful increases in breast cancer, coro? nary heart disease, stroke and pulmonary embolism, at? tributable to hormone therapy, convincingly offset the benefits of a reduced incidence of colorectal cancer and hip fracture. The study of combined estrogen and pro? gestin was ended early because of the strength of these findings, although the parallel WHI study of unopposed estrogen remains open. The current finding is important not only because the estimated effect for coronary heart disease is opposite that which was expected, but also because as many as 38% of postmenopausal women have been treated with hormone replacement therapy. This circumstance appears to represent what many observationalists had hoped would be a rare or impossible event, namely a strong discordance between risk estimates obtained from epidemiologic study designs and those obtained from randomized clinical trials (RCTs). In recent years, there has been a growing sentiment among some researchers that observational studies yield qualitatively and quantitatively similar estimates of treatment effects as RCTs. For example, a pair of papers written from this perspective was published 2 years ago in The New England Journal of Medicine S'5 Many readers understood these papers to support the idea that esti? mates of treatment effects from observational studies are similar to those from RCTs, calling into question the