The Children's Cancer Study Group instituted a pilot study to investigate the use of high doses of cytosine arabinoside (AraC) in the intensification phase of treatment for acute nonlymphocytic leukemia (ANLL). Patients achieving remission and not eligible for allogeneic bone marrow transplantation were treated with four doses of high-dose AraC and L-asparaginase. These drugs were repeated either on or after 28 days (q28 days), after recovery of hematologic parameters (for the first 49 patients entered onto this trial); or after 7 days (q7 days), despite dropping blood counts (for the last 53 patients enrolled). After completing an additional 3 months of intensification therapy, patients were then allocated by physician choice to either discontinue therapy or receive 18 28-day cycles of maintenance therapy, including the daily administration of 6-thioguanine. Despite three deaths associated with the toxicity of the aggressive (q7 days) AraC timing, patients receiving this approach demonstrated equal or better disease-free survival from the end of induction (55% versus 42% actuarially at 3 years [P = 0.52]). Maintenance therapy appeared to play no role in improving outcome for people who received the aggressive timing of AraC cycles. Fifty-nine percent were alive disease free actuarially at 3 years from the decision to not give maintenance therapy (n = 27) compared with 62% for those receiving maintenance therapy (n = 16; P = 0.49). On the other hand, patients who received the less aggressive AraC intensification timing (q28 days) had an improved survival rate if maintenance therapy was administered (n = 17) (65% versus 39% for patients not receiving maintenance therapy [n = 24] at 3 years [P = 0.07]). Maintenance therapy therefore may not improve outcome in patients receiving aggressive timing of high-dose AraC but may be important in less intensive postremission regimens in childhood ANLL.