For patients with hormone-receptor-positive breast cancer, the risk of relapse remains significant even after successfully completing 5 years of adjuvant tamoxifen. The use of tamoxifen beyond 5 years is not recommended, but the need to protect against relapse following tamoxifen is clear. The third-generation aromatase inhibitors offer a new approach to treating postmenopausal women with receptor-positive early stage breast cancer through the potent and specific systemic inhibition of estrogen synthesis. MA.17, a large, randomized, double-blind, placebo-controlled phase III study, investigated whether extended adjuvant therapy with letrozole following completion of around 5 years of standard tamoxifen therapy could prolong disease-free survival in postmenopausal women with hormone-receptor-positive or receptor-unknown early stage breast cancer. The updated analyses of the trial results (median follow-up, 2.5 years) confirm that letrozole significantly reduced the risk of recurrent breast cancer (42%) regardless of the patient's nodal status or receipt of prior chemotherapy, and significantly reduced the risk of distant metastasis (40%). Importantly, letrozole as extended adjuvant therapy achieved a significant improvement in overall survival in women with node-positive disease. Mortality was reduced by 39% among the approximately 2,500 women with node-positive disease randomized in the study. Letrozole showed minimal side effects compared with placebo; adverse effects on bone metabolism of uncertain clinical significance were the most noteworthy side effect. Thus, the updated results from the MA.17 trial support the previous findings and show extended adjuvant therapy with letrozole to be a well-tolerated protection against the continuing risk of breast cancer recurrence for thousands of women currently receiving standard adjuvant tamoxifen. The re-randomization of MA.17 patients to an additional 5 years of letrozole or to no treatment will provide further insights into the benefits and side effects of long-term treatment.