BACKGROUND: In the Postmenopausal Evaluation and Risk Reduction With Lasofoxifene (PEARL) trial, women assigned to lasofoxifene 0.5 mg/d had a lower risk of major coronary heart disease (CHD) events and stroke, whereas women assigned to lasofoxifene 0.25 mg/d had a lower risk of stroke. Both doses of lasofoxifene increased the risk of venous thromboembolic events. In this report, we provide comprehensive cardiovascular end-point data, including component events comprising the composite end point of major CHD events, and evaluate whether the effect of lasofoxifene 0.5 mg/d is consistent across different categories of CHD risk. METHODS AND RESULTS: In this study, 8556 women 59 to 80 years of age with osteoporosis received lasofoxifene 0.25 mg/d, lasofoxifene 0.5 mg/d, or placebo for 5 years. Cardiovascular events, including major CHD events, were prespecified secondary end points. Compared with placebo, lasofoxifene 0.5 mg/d reduced the risk of major CHD events 32% (hazard ratio, 0.68; 95% confidence interval, 0.50 to 0.93), including the risk of coronary revascularization (hazard ratio, 0.56, 95% confidence interval, 0.32 to 0.98). Reductions in risk of hospitalization for unstable angina (hazard ratio, 0.55; 95% confidence interval, 0.29 to 1.04) and diagnosis of new ischemic heart disease (hazard ratio, 0.52; 95% confidence interval, 0.26 to 1.04) nearly reached significance (P=0.06 for both comparisons). Although both hazard ratios were <1.0, no significant effect of lasofoxifene at 0.5 mg/d was demonstrated for coronary death or nonfatal myocardial infarction. The reduction in CHD events with lasofoxifene 0.25 mg/d was not significant (hazard ratio, 0.76; 95% confidence interval, 0.56 to 1.03; P=0.08). The effectiveness of lasofoxifene 0.5 mg/d in reducing CHD events was similar across strata of major cardiovascular risk factors. CONCLUSIONS: In postmenopausal women with osteoporosis, lasofoxifene 0.5 mg/d for 5 years reduced the risk of CHD events, regardless of the presence or absence of risk factors for cardiovascular disease. The significant reduction in risk of CHD events with lasofoxifene 0.5 mg/d was due primarily to lower risks of coronary revascularization procedures, hospitalization for unstable angina, and diagnosis of new ischemic heart disease. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00141323.