Imatinib results in significant and durable responses for CML. The safety of discontinuation has not been rigorously tested. In a prospective study, imatinib was discontinued among CML patients in a complete molecular remission (CMR) for 2 years or more. Among 69 patients with at least one year of follow-up, 61% relapsed by molecular analysis, almost all by 6 months. After imatinib reintroduction, all 42 relapsing patients responded, of which 26 (62%) entered CMR again. High Sokal score at baseline, female sex, and shorter period of CMR predicted for relapse on imatinib discontinuation. Around 40% of patients with CML in prolonged CMR on imatinib do not relapse at least one year after stopping the drug.