Acute myeloid leukemia associated with translocation t(8;21) and the underlying AML1-ETO gene fusion is considered as a distinct type of leukemia with characteristic morphologic features. Variant and masked forms of the classic translocation t(8;21) are uncommon and their clinicopathologic features are less well characterized. We report here a patient with a masked translocation involving chromosomes 6,8 and 21. Chromosomal study at diagnosis initially reported the karyotype as translocation between chromosomes 6 and 8 without visible involvement of chromosome 21. However, fluorescence in situ hybridization studies revealed the involvement of chromosome 21 in the translocation and presence of the AML1-ETO chimeric gene. The complex rearrangement t(6;8;21) observed in our patient was not previously described and could be not detected without combination of techniques. Our case illustrates the challenge of recognizing complex aberrations that occur with variant t(8;21) and further reinforces the utility of fluorescence in situ hybridization applications in more accurate characterization of chromosome abnormalities which can lead to more precise therapeutic stratification.