Five weekly doses of triple intrathecal (IT) chemotherapy (methotrexate, hydrocortisone, cytosine arabinoside) starting on day 1 of treatment were added to systemic induction therapy in a regimen (Arm 3) that was compared to three other regimens (Arms 1, 2, and 4) in which central nervous system (CNS) prophylaxis was initiated after complete marrow remission (CR) was attained. The CR rate for Arm 3 was only 83% as compared to 91-92% for other Arms. The lower CR rate was the result of a significantly higher death rate during induction for patients receiving early CNS prophylaxis (10.6 vs 0.9-3.5%). These differences were only observed in high risk patients as defined in the study. The early death rate was especially high (30%) in Arm 3 for children who were less than 2 years of age. Infection was the primary cause of morbidity and mortality. Severe infection following the initiation of induction therapy was found in 16.7% of patients on Arm 3 vs 1.8-6% on other regimens. Immediate triple IT chemoprophylaxis during induction therapy of acute lymphoblastic leukemia as used in this study appears to be associated with increased susceptibility to infection and this form of CNS prophylaxis has increased hazards of morbidity and mortality in infants and other high risk patients.