Purpose: The optimal adjuvant endocrine strategy for postmenopausal breast cancer is unknown. Options include the antiestrogen tamoxifen, estrogen deprivation with aromatase inhibitors, and sequential therapy with tamoxifen and then an aromatase inhibitor. Methods: We developed Markov models to simulate 10-year disease-free survival among postmenopausal women with hormone receptor-positive breast cancer. The treatment strategies analyzed were 5 years of tamoxifen alone, 5 years of an aromatase inhibitor alone, and sequential treatment consisting of tamoxifen with cross over to an aromatase inhibitor at 2.5 or 5 years. Risk estimates were derived from reported randomized clinical trials. Results: Sequential therapy with tamoxifen followed by cross over to an aromatase inhibitor at 2.5 years yielded a modest improvement in disease-free survival compared with planned aromatase inhibitor monotherapy. At 10 years, the cross-over strategy yielded absolute disease-free survival rates of 83.7% and 67.6% for node-negative and node-positive patients, respectively, compared with 82.6% and 65.5%, respectively, for aromatase inhibitor monotherapy, which is a 6% relative risk reduction. Sequential therapy improved disease-free survival estimates by year 6 after treatment initiation. Later cross over from tamoxifen to an aromatase inhibitor at 5 years did not further improve 10-year disease-free survival estimates. Sensitivity analyses suggest that sequential treatment strategies opti-mized 10-year disease-free and distant disease-free survival independent of the degree of the beneficial carryover effect after aromatase inhibitor therapy or the ratio of local to distant tumor recurrence. Conclusion: Modeling estimates suggest that sequential adjuvant therapy with tamoxifen followed by an aromatase inhibitor after 2.5 years yields improved outcomes compared with either drug alone or cross-over treatment after 5 years of tamoxifen.