The clinical, morphologic, and cytogenetic findings in a patient with acute megakaryoblastic leukemia (ANLL-M7) are described. At the time of diagnosis, the karyotype contained three related clones: 47,XY,t(3;6)(p13;q27), +8,t(12;22)(p13;q12), +15, -21, -22, +der(22)t(21;22)(q11;p13)/47,XY, +8,del(9)(q22),t(12;22), +15, -21, -22, +der(22)/46,XY, +8, t(12;22), -21, -22, +der(22). Complete remission was achieved with intensive combination chemotherapy. At relapse 20 months later, there was clear evidence of clonal evolution, and the karyotype was now 45,XY,t(2;18)(q33;p11),del(9)(q22),t(12;22)(p13;q12), -16, +der(16)t(8;16)(q13;p13), -21, -22, +der(22)t(21;22)(q11;p13)/46,XY,t(2;18),del(9),t(12;22), -16, +der(16), -21, -22, +der(22), +mar. A comparison with the few previously cytogenetically analyzed cases of ANLL-M7 reveals that structural rearrangements of chromosomes 21 and 22 might be of primary importance in the pathogenesis of acute megakaryoblastic leukemia.