The incidence of central nervous system (CNS) recurrence in patients with lymphoma is about 5%. Nevertheless, this complication is very serious because it is almost always fatal. Its incidence is not sufficiently high to warrant the use of CNS prophylaxis in all patients. The identification of subgroups for whom CNS prophylaxis may be of benefit is therefore important and the age-adjusted international prognostic index (aa-IPI) may be useful in this respect. Ifosfamide (IFO) is a widely used antitumor agent, requiring activation to isophosphoramide mustard (IPM) for DNA alkylation. IFO anabolism occurs through the hepatic microsomal cytochrome P450 system. As with the majority of antineoplastic agents, IFO has toxic side-effects. These include neurotoxicity due to the chloroacetaldehyde (CAA) catabolite. However, the incidence of neurotoxicity is low when IFO is administered as a continuous intravenous infusion. Both inactive IFO and active IPM cross the blood–brain barrier, making IFO treatment effective in the prevention of CNS metastasis in lymphoma patients at high risk of recurrence. The benefit/risk ratio for such patients should evaluated.