This controlled study of children with ALL was designed to determine in a prospective manner the relative efficacy and toxicity of two forms of "prophylactic" CNS therapy for preventing CNS relapse and of periodic vincristine-prednisone "pulses" during multiple agent chemotherapy. Following cranial irradiation (2400 rads) plus intrathecal methotrexate, 3 of 45 patients developed CNS leukemia. Following craniospinal irradiation (2400 rads), 2 of 49 developed CNS leukemia. Craniospinal irradiation was associated with more leukopenia and interruptions of chemotherapy. "Pulses" were not associated with improvement of remission duration. Our current choice of CNS therapy is cranial irradiation plus intrathecal methotrexate because it takes less time and may avoid demonstrated short-term side effects and possible long-term effects of spinal irradiation.