The outcome of B-cell non-Hodgkin lymphoma (B-NHL) in children and adolescents has improved significantly over recent decades due to risk-adapted strategies and the use of immunotherapy. However, refractory or relapsed (R/R) B-NHL remains extremely difficult to cure (<30%). This retrospective study of 45 patients with R/R B-NHL reflects the limited benefit associated with reintroducing rituximab in second-line strategies, the importance of achieving complete remission before stem cell transplantation and the potential role of TP53 as a biomarker in R/R B-NHL. TP53 mutations were identified in 44% of tumours and associated with a worse 3-year overall survival (15% vs. 80%; p = 0.048).