OBJECTIVES: Following the results of the phase III CLEOPATRA and EMELIA trials, a consensus has emerged regarding the optimal systemic treatment sequence for HER2-positive metastatic breast cancer (mBC). Although there has been a surge of novel treatment options in the United States (U.S.) for HER2-positive mBC over the past 20 years, there is also concern regarding increasing drug prices and the ability of public and private payers to reasonably keep up. This research aims to perform a cost-effectiveness analysis of different sequencing strategies of FDA-approved HER2 targeted agents.   METHODS: A model-based economic evaluation of four HER2 targeted treatment sequences was conducted following a U.S. Centers for Medicare and Medicaid Services (CMS) perspective and a lifetime horizon. Log-logistic models were fitted to survival distributions in published phase III trials. Cost data were captured from the CMS drug payment table and physician fee schedule. Benefits were expressed as quality-adjusted life years (QALYs), with utility weights obtained from regression analyses. The incremental cost-effectiveness ratios (ICERs) of the pairwise comparisons of the non-dominated options were estimated. Deterministic and probabilistic sensitivity analyses were conducted.  RESULTS: The combination of pertuzumab, trastuzumab and docetaxel (THP) as first line therapy, with T-DM1 as second line therapy, and lapatinib/caepcitabine as third-line resulted in 1.76 QALYs, at a cost of $322,913 per QALY gained. At progression, THP as first-line therapy without subsequent T-DM1 resulted in 1.48 QALYs, at a cost of $459,100 per QALY gained. The least clinically effective sequence, but most cost-effective at a total cost of $159,500, was found to be trastuzumab/docetaxel as first line, trastuzumab/lapatinib as second line, and trastuzumab/capecitabine as third line. CONCLUSIONS: THP followed by T-DM1 would require a reduction in drug price of approximately 50% to be cost-effective. This study offers a framework for establishing value-based pricing for sequencing for targeted therapy in oncology in the US.