Each of 105 children with advanced acute leukemia in relapse was randomly assigned to one of three treatment schedules utilizing L‐asparaginase. L‐asparaginase used alone induced bone marrow remissions in 43% of all cases and 54% of evaluable cases. L‐asparaginase combined with vincristine and prednisone induced remissions in a significantly greater number of children—50% of all cases and 77% of evaluable cases: There was a suggestive advantage in survival experience for patients receiving the 3‐drug combination compared with L‐asparaginase alone. Survival in this study population was clearly related to the length of disease prior to start of therapy, the longer survivals occurring in those with longer prestudy duration of disease. Fourteen of 17 children who had relapsed following inductions of remissions with the first course of L‐asparaginase treatment had remissions again following retreatment with a second course. These results indicate that L‐asparaginase has considerable therapeutic activity in children with advanced leukemia.