In this study, we tried to select a very small subset of children with acute lymphoblastic leukemia (ALL) at minimal risk of treatment failure - identified to not only by early response in vivo, one of the strongest predictors in the I-BFM-SG experience, but also by age, blood count and in particular high DNA content - which we treated with a reduced-intensity BFM schedule. The AIEOP-ALL 9501 study enrolled patients with standard-risk (SR) ALL, defined as: <20,000 WBC/mm3, age 1 to <6 years, non-T immunophenotype, DNA index between 1.16 and 1.6, non t(9;22), no extramedullary leukemia, good response to prednisone (PGR, defined as <1,000/mmc blasts in the peripheral blood after 7 days of prednisone and one injection of IT-MTX), CR at the end of induction therapy. Follow-up was updated at December,31st 2003 and median follow-up was 5.9 years. Treatment consisted of a modified BFM schedule: 3-drug (VCR + PDN + Erwinia ASP), 43-day induction, no phase IB, 4x2 g/m2 MTX, reinduction with protocol II followed by 6MP+MTX continuation therapy up to 2 years; CNS directed therapy consisted of IT-MTXx18. Between May 95 and August 2000, 137 patients were identified as SR (7.8% of the ALL-95 population), of whom 102 received the SR protocol and are here reported.Of them, 1 died in remission of septicemia, and 1 had developed a second malignant neoplasm (T-ALL after initial B-lineage ALL); 11 patients relapsed (bone marrow, n=8; central nervous system, n=1; marrow + testis, n=1; eye, n=1) and their re-treatment included chemotherapy only (n=3, 1 dead) or plus bone marrow transplant (n=8) either autologous (n=2) or allogeneic from matched (n=4, 1 dead) or partially matched (n=2) unrelated donor. The remaining 89 are in first CR; the probabilities (and related standard errors) of survival and event-free survival (EFS) were 97.0% (1.7) and 86.7% (3.5) at 5 years, 95.3% (2.4) and 86.7% (3.5) at 7 years, respectively. There was no difference in the outcome between the 56 females [7 events, 7-yrs EFS, 87.3 (4.5)] and the 46 males [6 events, 85.9 (5.4)]. Although most of the relapsed patients were rescued, the long-term EFS in this small, very selected group of patients remains inferior to expectance. Thus, alternative selection criteria, for instance related to minimal residual disease as in current AIEOP-ALL 2000, should be considered in order to address the issue of treatment reduction.