Early molecular response has been associated with clinical outcome in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors. The BCR-ABL1 transcript rate decline from baseline to 3 months has been demonstrated to be more predictive than a single BCR-ABL1 level at 3 months (M3). However, it cannot be used routinely because ABL1, as an internal gene control, is not reliable for BCR-ABL1 quantification above 10%. This study aimed to compare clinical outcome and molecular response of chronic phase CML patients, depending on the percentage of BCR-ABL1 transcript decrease from month 3 to month 6 using ABL1 as an internal control gene. Two hundred sixteen chronic phase CML patients treated with imatinib 400 mg for whom M3 and month 6 molecular data were available were included in the study. Associations with event-free (EFS), failure-free (FFS), progression-free (PFS), and overall survivals (OS) molecular response 4 log and 4.5 log were assessed. The percentage of BCR-ABL1 decline from month 3 to month 6 was significantly linked to the EFS and the FFS (p < 0.001). A common cut-off of 67% of decline predicted the better risk of event. Patients with a decrease below 67% have worse EFS and FFS as compared to those having a higher decrease (p < 0.001). The impact was confirmed by multivariate analysis. Since the slope between diagnosis and 3 months cannot be reliable using ABL1 as an internal gene control, the second decline rate of BCR-ABL1 transcript between month 3 and month 6 could efficiently identify patients at higher risk of event.