Cerebrospinal fluid beta-2-microglobulin (CSF-beta 2m) was measured longitudinally in 48 patients affected by acute lymphoblastic leukemia (ALL). Thirteen developed a central nervous system (CNS) involvement during the course of the disease; although moderately higher mean CSF-beta 2m levels were found in these subjects, no significant statistical differences were observed in comparison with patients without this complication and compared with the control group. No correlations were found between beta 2m and other biochemical parameters in CSF. Furthermore, CSF-beta 2m levels appeared to be influenced by previous combined chemoradiotherapeutic treatment for CNS prophylaxis, presence of meningeal non-neoplastic infiltrates, patients' ages, amount of CSF blasts, and their immunological phenotype. In particular, only clearly B-committed leukemic cells, when tested, showed a strong surface expression of beta 2m, as demonstrated by immunocytochemical detection of this protein on cell membrane. However, in specific cases, CSF beta 2m measurement and CSF/serum beta 2m ratio were helpful in diagnosing and monitoring isolated CNS disease. Such findings suggest that CSF-beta 2m assay may be a useful tool in the management of CNS involvement in the course of ALL in only selected patients, as several factors can modify the outcome.