Purpose: Infants with acute lymphoblastic leukemia (ALL) often enter remission; however, they have a high rate of relapse. To prevent relapse, infants' tolerance of and benefits from early intensive rotating drug pairs as part of therapy were studied. Methods: After prednisone, vincristine, asparaginase, and daunorubicin induction, 12 intensive treatments (ABACABACABAC) were administered in 30 weeks: A, intermediate dose methotrexate MTX) and intermediate dose mercaptopurine (MP); B, cytosine arabinoside (Ara-C) and daunorubicin (DNR); C, Ara-C and teniposide (VM-26). Triple intrathecal chemotherapy (Ara-C, MTX, and hydrocortisone) was administered for central nervous system prophylaxis. Continuation therapy consisted of weekly MTX and daily MP for a total of 130 weeks of continuous complete remission. Results: Thirty-three infants (1 year old or younger) with newly diagnosed ALL were treated. Two infants did not respond to induction, I died from sepsis during continuation, I received a bone marrow transplant, and 24 relapsed. Median time to relapse was 39 weeks. The event- free survival rate at 5 years was 17% (standard error ± 7.7%). The most significant toxicities occurred during intensification and included fever- neutropenia and bacterial sepsis. Conclusion: Although early intensive rotating therapy is tolerable, the relapse-free survival rate remains poor for infants treated with the schedule on this protocol.