The second-generation tyrosine kinase inhibitors (TKIs) (2G-TKIs) dasatinib (DAS) and nilotinib (NIL) yield faster responses in newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML) as compared with imatinib (IM); however, long-term safety of these agents is a growing concern. We identified 20 patients with CP-CML diagnosed between August 2013 and October 2016 who initiated 2G-TKIs and were then switched after optimal response at 3 months to IM. Second-generation TKIs initiated were DAS (n = 15), NIL (n = 3), or both sequentially due to intolerance (n = 1). One other patient initiated therapy with ponatinib on trial. Response was assessed by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) for BCR-ABL1 levels every 3 months and in patients with qRT-PCR values less than 10% at 3 months, IM was started at 400 mg/d. IM was well tolerated except in 2 patients who required dose-reduction and discontinuation due to grade 2 skin rash (1) and grade 2 anxiety (1). After initiation of IM therapy, the BCR-ABL1 qRT-PCR levels trended down as expected. At 12 months 16 (84.2%) of 19 evaluable patients showed a 3 log (major molecular remission) or better reduction in their PCR levels. In conclusion, this retrospective analysis shows that IM can be safely and effectively administered following optimal response to 2G-TKIs. A prospective trial exploring this approach is currently enrolling and will be needed to confirm the safety and efficacy of this therapeutic approach.