The objective of the study was to assess acute neurotoxicity associated with triple intrathecal therapy (TIT)±high-dose methotrexate (HD MTX) in children with acute lymphoblastic leukemia (ALL). 1395 children were enrolled on FRALLE 93 protocol from 1993 to 1999. Lower-risk group (LR, n = 182) were randomized to weekly low-dose MTX at 25 mg/m2/week (LD MTX, n = 81) or HD MTX at 1.5 g/m2/2 weeks × 6 (n = 77). Intermediate-risk group (IR, n = 672) were randomized to LD MTX (n = 290) or HD MTX at 8 g/m2/2 weeks × 4 (n = 316). Higher-risk group (HR, n = 541) prednisone-responder patients received LD MTX and cranial radiotherapy. HR group steroid resistant cases were grafted (autologous or allogenic). TIT (MTX, cytarabine and methylprednisolone) was given every 2 weeks during 16-18 weeks and every 3 months during maintenance therapy in LR and IR patients. 52 patients (3.7%) developed neurotoxicity. Isolated seizures: n = 15 (1.1%), peripheral and spinal neuropathy: n = 17 (1.2%) and encephalopathy: n = 20 (1.4%). Age > 10 years was significantly associated with neurotoxicity (P = 0.01) and use of HD MTX is associated with encephalopathy (P = 0.03). Sequels are reported respectively in 60 and 33% of spinal neuropathy and encephalopathy cases. Current strategies tailoring risk of neurological sequels has to be defined.