The role of hormone replacement therapy (HRT) in the prevention of cardiovascular disease has been controversial. In large observational studies, HRT appears to lower cardiovascular disease risk. However, prospective randomized trials do not substantiate this.We sought to characterize the use of HRT in women presenting with acute myocardial infarction and to investigate an association between HRT and inhospital or 30-day outcomes among women enrolled in the Global Use of Strategies to Open Occluded Coronary Arteries III (GUSTO-III) trial. Of the 15,059 patients in GUSTO-III, 4124 were women. Menopausal status, HRT use, and clinical outcomes data were prospectively collected.Postmenopausal women taking HRT were significantly younger than those not taking HRT, and US women were more likely to be prescribed HRT than non-US women. While unadjusted 30-day mortality was substantially lower in HRT patients (6.1% vs 12.7%, P < .001), HRT use was not independently predictive of mortality after correcting for baseline differences (χ(2) = 0.15, P = .70).Hormone replacement therapy appears to have no early mortality benefit in women sustaining acute myocardial infarction. These findings further challenge the role of HRT in cardiovascular medicine.