Among histological aggressive non-Hodgkin lymphomas (NHL), the overall risk of central nervous system (CNS) relapse is approximately 5%, a figure which is too low to offer prophylaxis to all patients. The aim of this work is to demonstrate the utility of flow cytometry (FCM) in detecting occult leptomeningeal disease in this subtype of NHL. We studied cerebrospinal fluid (CSF) involvement in 42 newly diagnosed aggressive NHL patients at risk for CNS involvement. We used multicolour FCM to detect CSF infiltrating neoplastic cells. Among the 42 patients studied, 11 had CSF involvement as detected by FCM. Of these, only four were also positive for conventional morphology (p=0.046). These results designate that FCM as the first choice technique in NHL CSF clinical cell analysis.