The importance of maintenance therapy for higher risk childhood acute lymphoblastic leukemia (ALL) is uncertain. Between 1992 and 2001 the Nordic Society for Pediatric Haematology/Oncology compared in a nonrandomized study conventional oral methotrexate (MTX)/6-mercaptopurine (6MP) maintenance therapy with a multidrug cyclic LSA2L2 regimen. 135 children with B-lineage ALL and a white blood count ≥50×109/L and 98 children with T-lineage ALL were included. Of the 234 patients, the 135 patients who received MTX/6MP maintenance therapy had a lower relapse risk than the 98 patients who received LSA2L2 maintenance therapy, which was the case for both B-lineage (27%±5% vs. 45%±9%; P=0.02) and T-lineage ALL (8%±5% vs. 21%±5%; P=0.12). In multivariate Cox regression analysis stratified for immune phenotype, a higher white blood count (P=0.01) and administration of LSA2L2 maintenance therapy (P=0.04) were both related to an increased risk of an event (overall P value of the Cox model: 0.003), whereas neither sex, age at diagnosis, administration of central nervous system irradiation, nor presence of a day 15 bone marrow with ≥25% versus <25% lymphoblasts were of statistical significance. These results indicate that oral MTX/6MP maintenance therapy administered after the first year of remission can improve the cure rates of children with T-lineage or with higher risk B-lineage ALL.