The World Health Organization Classification of Lymphoid Neoplasms identifies Burkitt's lymphoma/leukaemia (BL) as a single entity, characterized by unique clinical and genetic features that require specific high intensity chemotherapy regimens. Although remarkable successes in the treatment of the disease have been observed, when compared with paediatric patients, adults are less likely to reach stable complete remission. We investigated 32 BL cases, composed in equal part by adults and children that were treated with the French LMB regimen, for factors that may be implicated in chemoresistance. Immunohistochemical detection of procaspase-8, caspase-3a, survivin, p53, CD95, c-Flip and Phospho-RelA (Ser536) was investigated on paraffin-embedded tissues. The expression of c-Flip was found highly related to a poor prognosis, mostly characterized by adults with a chemoresistant disease, resulting in a high death rate within the first year of diagnosis. The 2-year overall survival with c-Flip expression was 24% compared with 93% in the absence of this marker (P = 0.04). All c-Flip-positive BL cases presented a nuclear Phospho-RelA (Ser536) localization, suggesting the presence of an active nuclear factor (NF)-kappa B transcription pathway. These findings show that c-Flip could be a reliable prognostic factor in BL, suggesting new therapeutic approaches that target the NF-kappa B pathway.