BACKGROUND: Hormone replacement therapy (HRT) was widely used among postmenopausal women until 2002 because observational studies suggested that HRT reduced cardiovascular risk. The Women's Health Initiative randomized trial reported opposite results in 2002, which caused HRT use to drop sharply. OBJECTIVE: We examine the relationship between HRT use and cardiovascular outcomes (deaths and nonfatal hospitalizations) in the entire US population, which has not been studied in prior clinical trials or observational studies. METHODS: We use an instrumental variables regression design to analyze the relationship between medication use, cardiovascular risk factors, and acute stroke and myocardial infarction event rates in women aged 40 to 79 years. The natural experiment of the 2002 decline in HRT usage mitigates confounding factors. We use US death records, hospital discharge data obtained from the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample, and nationally representative surveys of medication usage, and behavioral risk factors. RESULTS: Decreases in HRT use were not associated with statistically significant changes in hospitalizations or deaths due to acute stroke (0.000002, P = 0.999, 95% CI: -0.0027 to 0.0027). Decreased HRT use was associated with a decrease in the incidence of acute myocardial infarction (-0.0025 or -25 events/10,000 person-years, P = 0.021, 95% CI: -0.0047 to -0.0004). The results were similar in a sensitivity analysis using alternate data sources. CONCLUSIONS: Decreased HRT use was not associated with reduced acute stroke rate but was associated with a decreased acute myocardial infarction rate among women. Our results suggest that observational data can provide correct inferences on clinical outcomes in the overall population if a suitable natural experiment is identified.