Acute myeloblastic leukemia (AML) with tetraploidy is rare. There have been only six such cases studied with banding techniques in the literature. Two were diagnosed as having AML-M2 and found to have similar near-tetraploid karyotypes with t(8;21) and missing Y chromosomes. We report two further cases of AML with tetraploid or near-tetraploid clones characterized by two t(8;21) and other chromosomal changes. Their cytogenetic findings were compatible with the diagnosis of AML-M2. Giant and bizarre blasts were seen on bone marrow (BM) smears from both cases. Immunologically, the blasts express CD2, CD15, and HLA-DR in case 1 and CD2 and CD65 in case 2. Cytogenetic studies on BM cells at diagnosis revealed that both cases had three related abnormal clones besides a normal one: 46,XY,t(8;21) (2%)/46,idem,add(7)(q31)(6.8%)/92, idem x 2 (80.6%) for case 1; and 46,XX,t(8;21)(13.4%)/47, idem,+4 (46.3%)/94,idem x 2 (39.1%) for case 2. Flow cytometric analysis displayed two cell populations in the former: one was in the diploid range and the other was in the tetraploid range. The patients did not obtain complete remissions and survived four and six months, respectively. These results indicate that tetraploid or near-tetraploid clones are secondary events which are associated with t(8;21) leukemia and may be associated with poor prognostic significance.