The t(12;21)(p13;q22) with ETV6-RUNX1 fusion occurs in 25% of cases of B-cell precursor acute lymphoblastic leukemia (BCP-ALL); and is generally associated with favorable prognosis. However, 15-20% of the t(12;21)-positive cases are associated with high-risk disease due to for example slow early responses to therapy. It is well-known that development of overt leukemia in t(12;21)-positive ALL requires secondary chromosomal aberrations although the full spectrum of these cytogenetic alterations is yet unsettled, and also, how they may be associated with disease outcome. This report describes the case of an adolescent male with t(12;21)-positive ALL who displayed a G-banded karyotype initially interpreted as del(1)(p22p13) and del(15)(q15). The patient was treated according to NOPHO standard risk protocol at diagnosis, but had minimal residual disease (MRD) at 6,4% on day 29 as determined by flow cytometric immunophenotyping. Because of MRD level>0.1% he was then assigned as a high risk patient and received intensified chemotherapy accordingly. Further molecular cytogenetic studies and oligo-based aCGH (oaCGH) analysis characterized the acquired complex structural rearrangements on chromosomes 1 and 15, which can be described as der(1)del(1)(p13.1p31.1)t(1;15)(q42;q15) with concurrent deletions at 1q31.2-q31.3, 1q42.12-q43, and 15q15.1-q15.3. The unbalanced complex rearrangements have not been described previously. Extended locus-specific FISH analyses showed that the three deletions were on the same chromosome 1 homologue that was involved in the t(1;15), and that the deletion on chromosome 15 also was on the same chromosome 15 homologue as involved in the t(1;15). Together these findings show the great importance of the combined usage of molecular cytogenetic analyses and oaCGH analysis to enhance characterization of apparently simple G-banded karyotypes, and to provide a more complete spectrum of secondary chromosomal aberrations in high risk t(12;21)-positive BCP-ALLs.