60-80% of patients with a post-transplant B-lymphoproliferative disorder (PTLD) occurring after hematopoietic stem cell transplantation responded to anti-B cell monoclonal antibody therapy [1,2]. Therapeutic response occurs rapidly, within one week after the first infusion. Several predictive factors of rituximab failure have been identified, including the number of tumour sites, the magnitude of immunodepression, central nervous system (CNS) involvement and late-onset of PTLD. Relapse is unfrequent and usually occurs after completion of treatment. We describe an unusual outcome in a child who developed, during rituximab, fatal CNS lesions associated with a high cerebrospinal (CSF) EBV burden despite a complete remission (CR) after the first infusion.He was a 2.5-year-old boy with juvenile chronic myelomonocytic leukemia who was given an unrelated 5/6 HLAidentical cord blood transplantation. Graft-versus-host disease prophylaxis combined thymoglobulin, with cyclosporine and steroids. The immediate post transplantation follow-up was uneventful.On day þ87 post-transplant, the child presented with fever, nasal obstruction, and tonsil enlargement. A tonsil biopsy confirmed the diagnosis of diffuse B large-cell lymphoma, expressing CD20 with positive EBV in situ hybridization using an EBV-small encoded RNA probe. No other site was involved and cerebral magnetic resonance imaging (MRI) was normal. The EBV DNA loads measured with a Real-Time quantitative PCR [3] were high both in peripheral blood mononuclear cells (PBMC) (4,652 copies/mg DNA) and in serum (5,200 copies/ml). From day þ92 after transplantation, the patient received 4 weekly doses of rituximab (375 mg/m 2 per course) leading to complete resolution of fever, radiologic CR and decrease in DNA copy numbers within one week (736 copies/mg DNA in PBMC and 1,575 copies/ml in serum). Fever recurred the day before the fourth dose of rituximab followed by a progressive neurologic deterioration over one week. MRI on T2-weighted sequences revealed diffuse lesions of high-signal intensity in the central grey nuclei and subcortical white matter without contrast-enhancement on T1-weighted imaging. An extremely high level of EBV load (98,350 copies/mg DNA) was measured in the CSF, associated with an increment of EBV DNA levels predominating in serum (5,300 copies/ml). Neurologic status rapidly worsened and patient died on day þ127. Parents refused necropsy.Our patient showed all criteria of a good clinical, radiologic, and biological response after the first infusion of rituximab. Although there were no indications of CNS involvement at diagnosis, the hypothesis of a minimal CNS involvement not detected by radiologic techniques could not be excluded. The subsequent very high EBV DNA load in the CSF and rebound of EBV DNA load in serum at the time of neurologic symptoms strongly support a secondary tumour progression. Nevertheless, the diagnosis of an EBV-linked encephalitis could not be ruled out, because of the appearance of the MRI lesions. Moreover, EBV DNA quantificat...