Acute myeloid leukemia (AML) with the t(8;21) (q22;q22) creating the AML1-ETO fusion gene is a distinct type of AML generally associated with a favorable prognosis. The clinicopathologic features of AML carrying variant t(8;21) are less well characterized. We report 4 cases of AML characterized by ins(8;21)(q22;q22q22), t(1;21;8)(q25;q22;q22), t(8;11;21)(q22;q13;q22), and t(4;21;8;12)(q31.3;q22;q22;q15), respectively. Fluorescence in situ hybridization or reverse transcriptase-polymerase chain reaction assay confirmed the presence of AML1-ETO or its transcripts in 3 cases assessed. Each neoplasm had morphologic characteristics of AML associated with the t(8;21). The blasts in 2 cases expressed CD19. All patients were treated with combination chemotherapy and are in complete remission, despite 2 relapses in 1 patient, with a follow-up period ranging from 8 to 46 months. We conclude that cases of AML with variant t(8;21) display morphologic, immunophenotypic, and clinical features similar to classical cases. A combination of conventional cytogenetic, and molecular analyses allows identification of these variants.