Out of 76 pediatric cases of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) positive for ETV6/RUNX1 (previously TEL/AML1) resulting from t(12;21), 7 cases revealed coexistence of ETV6/RUNX1 and MLL aberrations. One case of der(21) duplication with ETV6/RUNX1 exhibited a novel MLL translocation variant t(6;11)(p21.1p23;q13q25), with translocation of 3' telomeric MLL and deletion of 5' centromeric MLL. Another case of der(21) duplication with ETV6/RUNX1 showed MLL rearrangement upon Southern blotting. The remaining five ETV6/RUNX1-positive cases had MLL allelic deletion. ETV6/RUNX1 and MLL aberration clone size in these cases was suggestive of ETV6/RUNX1 as an early primary event, originating in the embryonic or infant stage and developing into leukemia by later acquisition of MLL aberration, ETV6 loss, and ETV6/RUNX1 duplication as secondary events. To date, the prognosis has been favorable, which seems to be compatible with ETV6/RUNX1-positive ALL. We conclude that the cases with coexisting ETV6/RUNX1 and MLL aberrations probably exist as a small, hidden group of ETV6/RUNX1-positive BCP-ALL, which invites further investigation, in large series from different populations, to confirm the findings and establish the biological mechanisms and prognostic significance.