Cytogenetic analysis of an acute myeloid leukemia (AML-M1) showed the karyotype 53,XY, +6, +8,t(8;21)(q22;q22), +9, +10, +13, +19, +21. Only one AML with a massively hyperdiploid karyotype (> 50 chromosomes) and t(8;21) has been published before. A comparison of the two cases reveals similarities both with regard to the morphologic subtype (M1) and to which chromosomes were trisomic (+6, +8, +13, +19, and +21 were found in both cases). We surmise that the t(8;21) was the primary chromosomal abnormality and that the set of multiple trisomies occurred secondarily; this pattern of clonal evolution may have favored a more immature leukemic phenotype in these two cases than is regularly seen in t(8;21)-associated leukemias.