Variants of the t(8;21)(q22;q22) involving chromosomes 8, 21, and other chromosomes account for approximately 3% of all t(8;21)(q22;q22) in acute myeloid leukemia (AML) patients. In this paper, we report a case of AML-M2 with a t(8;12;21)(q22;p12 approximately p13;q22) associated with chromosomal abnormalities, including loss of the Y chromosome and trisomy 8q22 approximately qter. Using a dual-color fluorescence in situ hybridization (FISH) analysis with ETO and AML1 probes, we demonstrated an ETO/AML1 fusion signal on the derivative chromosome 8. Using whole painting probes for chromosomes 8 and 12, we demonstrated a three-way translocation, t(8;12;21)(q22;p12 approximately p13;q22). Reverse transcription polymerase chain reaction (RT-PCR) analysis showed the presence of AML1/ETO fusion transcript. The present case highlights the importance of the combination of approaches, i.e., standard karyotyping, FISH, and RT-PCR, for the detection of variants of t(8;21)(q22;q22), shedding light on region 8q22 approximately qter which could harbor potential genes responsible for leukemogenesis.