BACKGROUND: Currently available selective estrogen receptor modulators reduce the risk of breast cancer, but they are not widely used. In the Postmenopausal Evaluation and Risk-Reduction with Lasofoxifene (PEARL) trial, lasofoxifene was shown to reduce the risk of estrogen receptor-positive (ER+) breast cancer, nonvertebral and vertebral fractures, coronary artery disease, and stroke, but the effects on total breast cancer (invasive and ductal carcinoma in situ, ER+ and estrogen receptor-negative [ER-]) and ER+ invasive breast cancer are unknown. METHODS: Postmenopausal women (n = 8556) aged 59-80 years with low bone density and normal mammograms were randomly assigned to two doses of lasofoxifene (0.25 and 0.5 mg) or placebo. The primary endpoints of the PEARL trial were incidence of ER+ breast cancer and nonvertebral fractures at 5 years. A nested case-control study of 49 incident breast cancer case patients and 156 unaffected control subjects from the PEARL trial was performed to evaluate treatment effects on risk of total and ER+ invasive breast cancer by baseline serum estradiol and sex hormone-binding globulin levels using logistic regression models. Cox proportional hazards models were used to evaluate risk of total breast cancer and ER+ invasive breast cancer using intention-to-treat analysis. All statistical tests were two-sided. RESULTS: Breast cancer was confirmed in 49 women. Compared with placebo, 0.5 mg of lasofoxifene statistically significantly reduced the risk of total breast cancer by 79% (hazard ratio = 0.21; 95% confidence interval [CI] = 0.08 to 0.55) and ER+ invasive breast cancer by 83% (hazard ratio = 0.17; 95% CI = 0.05 to 0.57). The effects of 0.5 mg of lasofoxifene on total breast cancer were similar regardless of Gail score, whereas the effects were markedly stronger for women with baseline estradiol levels greater than the median (odds ratio = 0.11; 95% CI = 0.02 to 0.51) vs those with levels less than the median (odds ratio = 0.78; 95% CI = 0.16 to 3.79; P(interaction) = .04). CONCLUSION: A 0.5-mg dose of lasofoxifene appears to reduce the risks of both total and ER+ invasive breast cancer in postmenopausal women with osteoporosis.