OBJECTIVES: The 74-month follow-up of the BIG 1-98 trial reported improved overall survival (OS) for 5 years letrozole (LET) versus tamoxifen (TAM; hazard ratio 0.83; 95%CI 0.71, 0.97; P<0.05). The 100-month follow-up of the ATAC trial did not show a significant difference in OS for anastrozole (ANA) versus TAM. Using reported differences in OS, we estimated the incremental cost per quality-adjusted life-year (QALY) gained for 5 years LET or ANA versus 5 years TAM in postmenopausal women with endocrine-responsive breast cancer (ERBC), from a UK NHS perspective. METHODS: Annual survival probabilities postoperatively were extracted from BIG 1-98 and ATAC results. Survival was extrapolated to 20 years using data reported by the EBCTG for women receiving 5 years TAM. Conservatively, equivalent annual survival probabilities were assumed for TAM, LET, and ANA groups after follow-up. Published adverse event (AE) costs and 5-year costs for locoregional recurrence (LR) and metastases were applied. Published utility weights for disease-free survival with AEs, LR, and metastases were used. All costs and health benefits were discounted at 3.5% annually. RESULTS: Over a 20-year period, the discounted additional treatment costs are £3618 for LET and £3736 for ANA. When accounting for AEs and reduced BC recurrence, the total cost difference between LET and TAM is £2964, and between ANA and TAM is £2929. The model estimated a difference in discounted QALYs of 0.297 for LET versus TAM, with an incremental cost per QALY gained of £9999. The incremental cost per QALY gained for ANA versus TAM is £46,829. CONCLUSIONS: Using updated OS data, economic analysis of 5 years LET or ANA versus 5 years TAM in postmenopausal women with ERBC suggests that LET is substantially more cost-effective than ANA. The current analysis is consistent with earlier extrapolations based on differences in time to recurrence.