OBJECTIVES: To analyze the cost-effectiveness of imatinib as first-line therapy from 2016-2021 compared to physician’s choice of other approved second-generation tyrosine kinase inhibitors (TKIs) dasatinib or nilotinib in chronic myeloid leukemia in chronic-phase (CML-CP), once imatinb loses patent exclusivity. METHODS: A Markov model simulating “imatinib-first” compared to “physician choice” in treating CML-CP in 2016 through 5 years from the U.S. commercial payer perspective. In both approaches, if initial treatment fails, patients are switched to second-generation TKIs. Patients switch if they fail efficacy endpoints: 12-month complete cytogenetic response (CCyR); or 3-month early molecular response (EMR). Patients are then followed from switching through overall survival. They can also deteriorate to accelerated phase/blast crisis or death. The model assumes stabilized prices of second-generation TKIs, but adjusts the price of imatinib to be 100% of the branded price for first 6-months, 60-80% for the second 6-months and 10-30% thereafter based on patent expiration.  For each drug, probabilities of treatment choice, switching and failure were meta-analyzed from published clinical trials. Quality-adjusted life years (QALYs) were based on US-societal health utilities. Direct medical costs per patient were calcated from Marketscan commercial claims (2011-2012), including annual drug prices. 2013 U.S.-dollars and QALYs were discounted at 3%. Univariate and multivariate sensitivity analyses tested parameters with greatest impact on results. Findings were interpreted from a willingness-to-pay of $100,000/QALY. RESULTS: Based on a 12-month CCyR, imatinib-first ($270,772; 3.80 QALYs) was cost-effective compared to physician choice ($361,935; 3.93 QALYs), an incremental cost-effectiveness ratio (ICER) of $701,000/QALY. The ICER based on 3-month EMR was $470,000/QALY. Results were robust to uncertainty. The probabilistic sensitivity analysis demonstrated that imatinib-first was cost-effective in 99% of simulations. CONCLUSIONS: When imatinib loses patent protection in 2016 in the U.S. and its price declines, it will be the cost-effective treatment strategy for CML-CP compared to dasatinib and nilotinib.