Three patients with acute lymphoblastic leukemia (ALL) developed mononuclear cells in the cerebrospinal fluid (CSF) after a flu-like history during maintenance treatment. None of the patients showed evidence of central nervous system (CNS) involvement by either clinical or laboratory follow-up. Although the presence of > 5 mononuclear cells/microl in the CSF is important, it may not necessarily indicate CNS disease. Clinical findings, history and cell morphology must be evaluated before deciding on further treatment.