<jats:title>Abstract</jats:title><jats:p>Treatment‐free remission (TFR) by tyrosine kinase inhibitors (TKI) discontinuation in patients with deep molecular response (DMR) is a paramount goal in the current chronic myeloid leukemia (CML) therapeutic strategy. The best DMR level by real‐time quantitative PCR (RT‐qPCR) for TKI discontinuation is still a matter of debate. To compare the accuracy of digital PCR (dPCR) and RT‐qPCR for <jats:italic>BCR‐ABL1</jats:italic> transcript levels detection, 142 CML patients were monitored for a median time of 24 months. Digital PCR detected <jats:italic>BCR‐ABL1 </jats:italic>transcripts in the RT‐qPCR undetectable cases. The dPCR analysis of the samples, grouped by the MR classes, revealed a significant difference between MR<jats:sup>4.0</jats:sup> and MR<jats:sup>4.5</jats:sup> (<jats:italic>P</jats:italic> = 0.0104) or MR<jats:sup>5.0</jats:sup> (<jats:italic>P</jats:italic> = 0.0032). The clinical and hematological characteristics of the patients grouped according to DMR classes (MR<jats:sup>4.0</jats:sup> vs MR<jats:sup>4.5‐5.0</jats:sup>) were superimposable. Conversely, patients with dPCR values <0.468 <jats:italic>BCR‐ABL1</jats:italic> copies/µL (as we previously described) showed a longer DMR duration (<jats:italic>P</jats:italic> = 0.0220) and mainly belonged to MR<jats:sup>4.5‐5.0</jats:sup> (<jats:italic>P</jats:italic> = 0.0442) classes compared to patients with higher dPCR values. Among the 142 patients, 111 (78%) discontinued the TKI treatment; among the 111 patients, 24 (22%) lost the MR<jats:sup>3.0 </jats:sup>or MR<jats:sup>4.0</jats:sup>. RT‐qPCR was not able to discriminate patients with higher risk of MR loss after discontinuation (<jats:italic>P</jats:italic> = 0.8100). On the contrary, according to dPCR, 12/25 (48%) patients with <jats:italic>BCR‐ABL1</jats:italic> values ≥0.468 and 12/86 (14%) patients with <jats:italic>BCR‐ABL1</jats:italic> values <0.468 lost DMR in this cohort, respectively (<jats:italic>P</jats:italic> = 0.0003). Treatment‐free remission of patients who discontinued TKI with a dPCR <0.468 was significantly higher compared to patients with dPCR ≥ 0.468 (TFR at 2 years 83% vs 52% <jats:italic>P</jats:italic> = 0.0017, respectively). In conclusion, dPCR resulted in an improved recognition of stable DMR and of candidates to TKI discontinuation.</jats:p>