ABSTRACT: The cost of tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML) is a substantial economic burden. In Japan, imatinib, dasatinib, and nilotinib are now approved as first-line treatment of CML in chronic phase. Recent "stop TKI" trials have shown that TKIs can be safely discontinued in nearly one-half of patients with sustained deep molecular response (DMR). In this study, we analyzed the cost-effectiveness of a simulated 10 years of CML treatment including stop TKI in both the United States and Japan. We constructed Markov models to compare 4 strategies in which treatment was initiated with imatinib, dasatinib, nilotinib, or any of these TKIs at the physician's discretion. Treatment was switched to another TKI in the case of intolerance or resistance to the initial TKI, and TKIs were discontinued if DMR persisted for 2 years. "Imatinib first" offered 7.34 quality-adjusted life years (QALYs) at the cost of $1?022?148 in the United States (US dollars) and ¥32?526?785 in Japan (Japanese yen). In comparison with imatinib first, the incremental cost-effectiveness ratio per QALY of "dasatinib first" (7.68 QALY, $1?236?052, ¥51?506?254), "nilotinib first" (7.64 QALY, $1?245?667, ¥39?635?598), and "physician's choice" (7.55 QALY, $1?167?818, ¥41?187?740) was $641?324, $696?717, and $666?634 in the United States and ¥54?456?325, ¥23?154?465, and ¥39?635?615 in Japan, respectively. None of the 3 strategies met the willingness-to-pay threshold. The results were robust to univariate and multivariate sensitivity analyses. Imatinib first was shown to be the most cost-effective approach even with the incorporation of stop TKI.