Leptomeningeal involvement (LI) is a rare complication in the course of B-cell chronic lymphocytic leukemia (CLL). It is difficult to assess, thus several cases may go unrecognized. Here we report on six patients with LI of B-CLL. Neurologic symptoms were present in five of six patients. Cerebral MRI, although performed in all subjects, was diagnostic in two patients only. Examination of cerebrospinal fluid by cytology and immunophenotyping revealed LI in all six cases. One patient received whole brain irradiation, two patients received intrathecal therapy or intravenous fludarabine respectively. Clinical responses occurred in one patient after irradiation and two patients after fludarabine. Response in CSF was observed in all four evaluable patients after intrathecal therapy (n=2) and fludarabine (n=2). Survival for the patient who received irradiation was five months and for the two patients treated with intrathecal therapy three and six months respectively. One of the patients on fludarabine treatment survived for 21 months with an 11 month event-free survival for the CNS manifestations while the other patient has been in an ongoing meningeal CR and hematologic PR for 20 months. We conclude that fludarabine may be useful in meningeal involvement of CLL with impact on systemic disease.