Summary Burkitt lymphoma (BL) and Diffuse Large B‐Cell Lymphoma (DLBCL) account for most cases of non‐Hodgkin lymphoma (NHL) in childhood. We report the clinical characteristics, outcome and prognostic factors in children with BL or DLBCL treated according to the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) LNH‐97 protocol. Patients aged up to 18 years that were newly diagnosed with BL/DLBCL were included in the study. Therapy consisted of pre‐phase followed by 2–6 high‐dose chemotherapy courses tailored according to lactate dehydrogenase (LDH) value and disease stage. A total of 442 patients (379 BL, 63 DLBCL) were enrolled between 1997 and 2014, of whom 18 failed to achieve remission, 6 experienced treatment‐related death, 2 developed second malignancy and 20 relapsed. At a median follow‐up time of 5 years, overall survival was 93% (±1%) and event‐free survival was 90% (±1%). LDH value above the median value had an independently negative prognostic value (P < 0·0001). However, in the subgroup of 128 patients in which minimal disseminated disease (MDD) was analysed, MDD‐positivity became the only unfavourable prognostic factor for progression‐free survival. Tailored chemotherapy could be extremely effective with limited toxicity. Identification of MDD as a hallmark of a higher risk of treatment failure may provide a target population for treatment intensification by anti‐CD20.