This study was designed to determine if resistance to a standard drug during the second remission of children with acute leukemia was reduced by discontinuation of therapy during the initial remission. The initial maintenance therapy was either 6-mercaptopurine (6-MP), methotrexate (MTX), or cyclophosphamide (CYC) given continuously to relapse or discontinued (at random) at 2 or 6 months. Following the initial relapse and after induction of a second complete remission, 72 evaluable patients received (continuously to relapse) either 6-MP (53 patients) or CYC (19 patients) for the second remission maintenance. Resistance of 6-MP occurred during the second maintenance, regardless of the drug used during the initial maintenance, in that the length of second remissions was significantly shorter than the length of first remissions. However, this resistance was most pronounced in patients who initially relapsed while on continuous 6-MP maintenance (medium duration of remission [MDR] of 9 weeks). Patients whose initial relapse occurred after the discontinuation of 6-MP had a MDR of 23 weeks and patients whose second remission was maintained with CYC (after relapse from initial continuous remission on 6-MP) had a MDR of 25 weeks.