Isolated central nervous system (CNS) relapse was evaluated in terms of incidence, risk factors, and outcome in a consecutive cohort of 175 patients with aggressive non-Hodgkin's lymphoma in which no case of lymphoblastic or Burkitt's lymphoma was encountered. All these patients had obtained a complete remission with first-line treatment and none had received prophylactic CNS treatment at diagnosis. Nine patients (5.2%) developed isolated CNS relapse after a median of 8 months from diagnosis. CNS involvement was documented by cerebrospinal fluid (CSF) cytology in 4 patients and on the basis of radiologic and clinical features in 5 others. Factors significantly associated with a greater likelihood of CNS relapse were advanced stage, B symptoms, bone marrow involvement, and high LDH levels in univariate analysis with only advanced stage being of significance in multivariate analysis. All relapsed CNS lymphoma patients died within a median time of 4 months from the disease recurrence, confirming the poor prognosis after CNS relapse and stressing the need to develop new treatment strategies for patients at high risk of CNS recurrence.