I congratulate Baik et al, the authors of this eye-catching study 1 for their thoughtful organization of the results and for wrestling such a large dataset to the ground. I have two observations about the results that might have been included in a more extensive discussion of limitations. First, the size of this data set is indeed advantageous for allowing meaningful analysis of multiple stratifications; however, it also results in very large numbers of statistically significant findings that are, arguably, too small to be of clinical significance, and actually make it harder to understand which associations are likely to be the most robust. Can you describe in more detail how you came to understand the influence of the hundreds of simultaneous statistical tests? There are >400 statistical tests in the data displayed in the manuscript alone.More importantly, some of the results are difficult to reconcile with our understanding of the biology of menopause hormone therapy and therefore increase the concern that these associations are the result of unrecognized confounders. One that was most striking to me was the association of vaginal hormone therapy with the lowest risk of all-cause mortality in the estrogen-only group. Because vaginal estrogen is generally minimally absorbed systemically, it would be difficult to explain how users of vaginal estrogen alone were getting the largest magnitude mortality advantages from hormone therapy. It is interesting to note that the source of this large mortality advantage does not seem to show up in the marginal effects in the risks of cancer or cardiovascular disease tables. Because fracture risk (which is an important mediator of improved all-cause mortality in women on menopausal hormone therapy) was not mentioned anywhere in the study, I am guessing that data were not available to you or not suitable for analysis?Finally, as was eventually understood about other large, observational studies 2 after the surprising initial results of the WHI, users of hormone therapy have other, likely socioeconomic and behavioral, reasons why incidences of cardiovascular diseases and all-cause mortality rates are lower. Please comment on how likely your analysis was to be affected by that issue.Thank you for all of the effort that went into this study and for raising the profile of a dataset that clearly has value for those who are interested in studying the long-term effects of menopause hormone therapy.