Imatinib is an oral tyrosine kinase inhibitor and considered to be the most successful targeted anticancer agent yet developed given its substantial efficacy in treating chronic myeloid leukemia (CML) and other malignant diseases. In the USA and the EU, Novartis’ composition of matter patent on imatinib will expire in 2016. The potential impact on health system spending levels for CML after generic imatinib becomes available is the subject of considerable interest among stakeholders including physicians, payers, and patients. The extent of the potential savings largely depends on whether and to what extent prices decline and use stays the same or even increases. These are also empirical questions since the likely spending implications following generic imatinib’s availability are predicated on multiple factors: physicians’ willingness to prescribe generic imatinib, molecule characteristics, and health system priorities. This article discusses each of these issues in turn and their implications for the development of country-specific cost-effectiveness models to predict the implications for cost and quality of care from generic imatinib. Finally, we present a US-specific empirical analysis of the potential impact of generic imatinib on the cost-effective treatment of incident chronic myeloid leukemia in chronic phase (CML-CP). In the year following generic entry in the USA, imatinib’s price is expected to drop 70–90 %. We hypothesized that initiating treatment with generic imatinib in these patients and then switching to the other tyrosine kinase inhibitors (TKIs) dasatinib or nilotinib because of intolerance or lack of effectiveness (i.e., “imatinib-first”) would be cost-effective compared to the current standard of care – “physician’s choice” of initiating treatment with any one of the 3 TKIs. We find that the imatinib-first ($277,401; 3.87 quality-adjusted life years, QALYs) strategy offered patients nearly equivalent benefit at a savings of $88,343 over 5 years to US payers compared to the physician’s choice strategy ($365,744; 3.97 QALYs). The imatinib-first incremental cost-effectiveness ratio was approximately $884,000/QALY. The results were robust to multiple sensitivity analyses. We conclude that when imatinib loses patent protection and its price declines in the USA, its use will be the cost-effective initial treatment strategy for CML-CP. We look forward to observing the actual responses of US and EU stakeholders to imatinib’s loss of patent exclusivity over the next several years.