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Summary Background The optimal duration of extended therapy with aromatase inhibitors in patients with postmenopausal breast cancer is unknown. In the NSABP B-42 study, we aimed to determine whether extended letrozole treatment improves disease-free survival after 5 years of aromatase inhibitor-based therapy in women with postmenopausal breast cancer. Methods This randomized, double-blind, placebo-controlled, phase 3 trial was done in 158 centers in the USA, Canada, and Ireland. Postmenopausal women with stage I–IIIA hormone receptor-positive breast cancer, who were disease-free after about 5 years of treatment with an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor, were randomly assigned (1:1) to receive 5 years of letrozole (2·5 mg orally per day) or placebo. Randomization was stratified by pathological node status, previous tamoxifen use, and lowest bone mineral density T score in the lumbosacral spine, total hip, or femoral neck. The primary endpoint was disease-free survival, defined as time from randomization to breast cancer recurrence, second primary malignancy, or death, and was analysed by intention to treat. Primary endpoint was DFS, defined as time from randomization to BC recurrence, second primary malignancy, or death, and analyzed by intention to treat. To adjust for interim analyses, two-sided statistical significance level for DFS was set at 0.0418. ClinicalTrials.gov, ; active; no longer enrolling patients. Findings Between Sept 28, 2006, and Jan 6, 2010, 3966 patients were randomly assigned to receive letrozole (n=1983) or placebo (n=1983). Follow-up information was available for 3903 patients for the analyses of disease-free survival. Median follow-up was 6·9 years (IQR 6·1–7·5). Letrozole treatment did not significantly improve disease-free survival (339 disease-free survival events were reported in the placebo group and 292 disease-free survival events were reported in the letrozole group; hazard ratio 0·85, 95% CI 0·73–0·999; p=0·048). 7-year disease-free survival estimate was 81·3% (95% CI 79·3–83·1) in the placebo group and 84·7% (82·9–86·4) in the letrozole group. The most common grade 3 adverse events were arthralgia (47 [2%] of 1933 patients in the placebo group vs 50 [3%] of 1941 patients in the letrozole group) and back pain (44 [2%] vs 38 [2%]). The most common grade 4 adverse event in the placebo group was thromboembolic event (eight [<1%]) and the most common grade 4 adverse events in the letrozole group were urinary tract infection, hypokalemia, and left ventricular systolic dysfunction (four [<1%] each). Interpretation After five years of aromatase inhibitor-based therapy, five years of letrozole therapy did not significantly prolong disease-free survival compared with placebo. Careful assessment of potential risks and benefits is required before recommending extended letrozole therapy to patients with early-stage BC.