To estimate the effects on survival, quality-adjusted survival, and health care costs of using tamoxifen for primary prevention in subgroups of women at very high risk for breast cancer.A decision analysis was performed using a hypothetical cohort of women that included subgroups with atypical hyperplasia, Gail risk greater than 5, lobular carcinoma-in-situ, or two or more first-degree relatives with breast cancer. Data sources were the Breast Cancer Prevention Trial, the Surveillance, Epidemiology, and End-Results program, time trade-off preference ratings, the Group Health Cooperative of Puget Sound, and the United States Health Care Financing Administration.Our model predicted that tamoxifen would prolong the average survival of cohort members initiating use at ages 35, 50, and 60 years by 70, 42, and 27 days, respectively. It would prolong survival even more for those in the higher-risk groups, especially those with atypical hyperplasia (202, 89, and 45 days). Tamoxifen use was also projected to extend quality-adjusted survival by 158, 80, and 50 days in the atypical hyperplasia group. For younger women in the highest risk groups, chemoprevention with tamoxifen was estimated to have cost savings or be cost-effective, both with and without quality adjustments.Chemoprevention with tamoxifen may be particularly beneficial to women with atypical hyperplasia, 5-year Gail model risk greater than 5%, lobular carcinoma-in-situ, or two or more first-degree relatives with breast cancer. The benefits may be greater if tamoxifen is initiated before age 50 years rather than after and if the breast cancer risk reduction conferred by tamoxifen lasts longer than 5 years. For women with a very high risk of invasive breast cancer, chemoprevention with tamoxifen seems to be cost-effective.