Background: Imatinib revolutionized the treatment of CML demonstrating improved survival and durable response to treatment. Earlier and deeper response rates were observed with dasatinib and nilotinib in the front line setting compared to imatinib. Multiple clinical trials have revealed that carefully selected patients may safely discontinue TKI therapy. However, lifelong TKI therapy remains the standard of care outside of clinical trial. Methods: We reviewed the charts of patients with chronic phase CML treated with imatinib, dasatinib or nilotinib for chronic phase CML between January 2010 and April 2015 and identified 29 patients that had discontinued therapy. We collected data on their treatment history, response to therapy, and outcomes following TKI withdrawal. Results: At the time of TKI cessation all the patients had achieved an MMR (MR4) for at least 2 years. The median time in MMR prior to treatment withdrawal was 64 months. Twelve patients were treated with imatinib, 7 were treated with dasatinib, and 10 were treated with nilotinib. More than half the patients had received prior treatment with an alternative TKI. At the time of data collection, 18 patients (55%) remained in MMR off therapy. The median time off treatment at was 7 months (range 3-24 months). The median time to loss of MMR was 5 months (range: 2-11 months). No significant difference was observed between TKI and time to loss of MMR. Of those patients who lost MRR while off therapy, all achieved a second MMR upon resuming TKI therapy. Based on the average wholesale price, $3,149,576 was saved by cessation of TKI therapy during the observed period. Addition follow up and PCR testing accounted for an additional cost of $84,200 for a net saving of $3,065,376. Conclusions: TKI therapy can be safely discontinued in patients with an MMR duration more than two years with close follow up. The results of this retrospective study support discontinuation of TKI therapy outside of a clinical trial. With the life expectancy of patients with chronic phase CML now approaching that of the healthy population, lifelong use of TKI has important implications for patients in terms of medical costs and quality of life.