BACKGROUND:: The Women's Health Initiative randomized trial found greater coronary heart disease (CHD) risk in women assigned to estrogen/progestin therapy than in those assigned to placebo. Observational studies had previously suggested reduced CHD risk in hormone users. METHODS:: Using data from the observational Nursesĝ€™ Health Study, we emulated the design and intention-to-treat (ITT) analysis of the randomized trial. The observational study was conceptualized as a sequence of ĝ€ trials,ĝ€ in which eligible women were classified as initiators or noninitiators of estrogen/progestin therapy. RESULTS:: The ITT hazard ratios (HRs) (95% confidence intervals) of CHD for initiators versus noninitiators were 1.42 (0.92ĝ€"2.20) for the first 2 years, and 0.96 (0.78ĝ€"1.18) for the entire follow-up. The ITT HRs were 0.84 (0.61ĝ€"1.14) in women within 10 years of menopause, and 1.12 (0.84ĝ€"1.48) in the others (P value for interaction ≤ 0.08). These ITT estimates are similar to those from the Women's Health Initiative. Because the ITT approach causes severe treatment misclassification, we also estimated adherence-adjusted effects by inverse probability weighting. The HRs were 1.61 (0.97ĝ€"2.66) for the first 2 years, and 0.98 (0.66ĝ€"1.49) for the entire follow-up. The HRs were 0.54 (0.19ĝ€"1.51) in women within 10 years after menopause, and 1.20 (0.78ĝ€"1.84) in others (P value for interaction ≤ 0.01). We also present comparisons between these estimates and previously reported Nursesĝ€™ Health Study estimates. CONCLUSIONS:: Our findings suggest that the discrepancies between the Women's Health Initiative and Nursesĝ€™ Health Study ITT estimates could be largely explained by differences in the distribution of time since menopause and length of follow-up.