Abstract Women carrying germline BRCA1/2 deleterious mutations are an extreme risk population for developing breast cancer, with a cumulative life-time risk of 56-80%. Prophylactic bilateral mastectomy provides a valid option for reducing the risk of breast cancer by nearly 90 %. Although it greatly affects the quality of life, breast prophylactic surgery in BRCA1/2 mutation carriers have increased in Europe and in US over the last decade.The major breast cancer prevention trials using tamoxifen and raloxifen showed an approximately 50% risk reduction in high risk women. The contralateral risk reduction in current adjuvant trials comparing aromatase inhibitors (AI) to tamoxifen therapies reveals a higher preventive efficacy of AI after menopause. Two ongoing randomized studies using exemestane (MAP3) or anastrozole (IBIS2) are assessing the risk reduction of breast cancer in menopausal women but none are designed for BRCA1/2 carriers.The French federation of cancer centres, "FNCLCC" (Federation Nationale des Centres de Lutte Contre le Cancer) has developed a randomized phase III study to determine the efficacy of the aromatase inhibitor letrozole to reduce the incidence of invasive breast cancer in post menopausal BRCA1/2 carriers. The ONCO-03 (LIBER) study is a double-blind, letrozole versus placebo, controlled study involving 28 centres in France. The study opened for recruitment in march 2008. The study design, procedures and first analysis of patients enrolment are presented.Based on the known preclinical and clinical profile of AI, a greater reduction in breast cancer incidence with fewer side effects is hypothesized with this class of agents than with tamoxifen or raloxifen. For postmenopausal women bearing a BRCA1/2 genetic predisposition, prevention of breast cancer risk by letrozole could provide a precious alternative to bilateral mastectomy. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1048.