Post-transplant lymphoproliferative disorders (PTLD) represent an heterogeneous group of abnormal lymphoid proliferation related to Epstein-Barr virus (EBV) reactivation that arise early after allogeneic hematopoietic stem cell transplant (HSCT). PLTD with central nervous system (CNS) involvement has been reported in few cases. We describe the case of a 31-year-old-man who developed an EBV-related PTLD with CNS involvement 2 months after an allogeneic unrelated HSCT for acute myeloid leukemia in first complete remission who was successfully treated with rituximab, cidofovir and intrathecal infusion of methotrexate and methylprednisolone.