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Introduction Since 2009, multiple randomized trials have shown faster and deeper responses in CML patients treated with new-generation TKI (NG-TKI) compared to those treated with imatinib (IM). Are the same results observed in the general population? Materials and methods Patients were identified from the three French hematological malignancies population-based registries. All CML patients (ICD-O-3: 9875/3) diagnosed between 2006 and 2016 and resided in registries areas were included. The TKI generation effect on achievement of MMR in first-line therapy was assessed through a multivariate competitive risk analysis. An alluvial plot described the pathways leading to death. Results In total, 507 CML patients received TKI in first-line treatment, 22% were enrolled in a clinical trial. After adjustment, NG-TKI patients were significantly more likely to achieve MMR during first-line therapy than IM patients (HR: 1.88 CI95% [1.35-2.61]). At the end of follow-up, 212 patients were still in first-line therapy (46 of them died), 203 switched to second-line (43 subsequently died), 26 were on TFR from first-line (4 subsequently died), and 20 stopped their treatment (16 subsequently died). Discussion In this comprehensive real-life setting, the results were consistent with clinical trials. The results are not sufficient to conclude that a NG-TKI treatment is superior with regard to these patients, despite indications regarding differences between the TKI generation effect on survival and tolerance.