Risk-adjusted treatment stratification in T-cell acute lymphoblastic leukemias (T-ALLs) is currently based only on early response to chemotherapy. We investigated the prognostic implication of hyperactivation of NOTCH pathway resulting from mutations of NOTCH1 or FBXW7 in children with T-ALL enrolled in EORTC-CLG trials. Overall, 80 out of 134 (60%) patients were NOTCH+(NOTCH1 and/or FBXW7 mutated). Although clinical presentations were not significantly associated with NOTCH status, NOTCH+ patients showed a better early response to chemotherapy as compared with NOTCH− patients, according to the rate of poor pre-phase ‘responders’(25% versus 44%; P= 0.02) and the incidence of high minimal residual disease (MRD) levels (11%(7/62) versus 32%(10/31); P= 0.01) at completion of induction. However, the outcome of NOTCH+ patients was similar to that of NOTCH− patients, with a 5-year event-free survival (EFS) of 73% and 70%(P= 0.82), and 5-year overall survival of 82% and 79%(P= 0.62), respectively. In patients with high MRD levels, the 5-year EFS rate was 0%(NOTCH+) versus 42%(NOTCH−), whereas in those with low MRD levels, the outcome was similar: 76%(NOTCH+) versus 78%(NOTCH−). The incidence of isolated central nervous system (CNS) relapses was relatively high in NOTCH1+ patients (8.3%), which could be related to a higher propensity of NOTCH+ leukemic blasts to target the CNS.