Importance: Imatinib introduced a paradigm shift in the treatment of patients with chronic myeloid leukemia (CML), allowing a lifespan that is almost comparable to the general population. However, the health care expenditures associated with imatinib have increased steadily since its introduction in 2001. Since the generic market entry of imatinib on February 1, 2016, it became possible to determine the effect of generic entry on the health care expenditures associated with imatinib, along with the concurrent pricing trends of second-generation tyrosine kinase inhibitors (TKIs). Objective: To compare health care expenditure related to imatinib treatment for patients with CML prior to its generic status with expenditures after, in a real-world setting. Design, Setting, and Participants: A retrospective cohort study using data from the Truven Health MarketScan Database was carried out including 1301 commercially insured patients or patients with Medicaid between the ages of 18 and 64 years with a CML diagnosis between September 1, 2014 and December 31, 2017. A single interrupted time series (ITS) method was used to evaluate monthly expenditures associated with imatinib for the health plan from September 1, 2014 to December 31, 2017, with imatinib switching to generic on February 1, 2016, as the interruption. The initial 6-month period postinterruption was excluded to allow for the new price structure to stabilize. Nilotinib and dasatinib were evaluated using a comparative ITS design. The analysis took place between September 1, 2014 to December 31, 2017. Main Outcomes and Measures: Commercial and Medicaid health plan expenditure and patient cost responsibility for 30-day blocks per patient for imatinib, dasatinib, and nilotinib were calculated from September 1, 2014 through December 31, 2017. Pricing was adjusted via 2017 consumer price index for medical services. Results: The sample included a total of 1301 patients (1102 commercially insured and 199 insured through Medicaid) with a median (range) age at diagnosis of 50 (18-62) years for commercially insured patients and 50 (47-52) years for patients with Medicaid. Of the 1301 patients, 704 (54.1%) were men. There was a significant pregeneric increase in expenditure (commercially insured: $143 per patient per month, P <.001; Medicaid: $152 per patient per month, P =.001). There was a significant reduction over the 6-month interruption period (February 2016 through August 2016) between the pregeneric and generic phase (commercial: $-3097 per patient, P <.001; Medicaid: $-2077 per patient, P =.002). Controlling for secular trends, this was followed by a small decline in expenditure during the generic phase (commercially insured: -$93 per patient per month; P =.03; Medicaid: -$182 per patient per month; P =.001). Nilotinib and dasatinib maintained an increasing trend in both the pregeneric and generic phase of imatinib, resulting in a significant difference-in-difference slope for commercially insured patients (nilotinib: -$186, P =.006; dasatinib: -$175, P =.007) and patients with Medicaid (nilotinib: -$299, P =.002; dasatinib: -$329, P <.001). There were no significant trends for patient cost responsibility. Conclusions and Relevance: The modest decline in expenditure associated with imatinib after generic entry accompanied by the increasing expenditure trends associated with the second-generation TKIs suggest a need for measures to facilitate cost reduction as well as standardization of CML treatment..