Variants of t(8;21)(q22;q22) account for approximately 3% of all t(8;21) in acute myeloid leukemia (AML). We report a 63-year-old female patient with AML, who showed a 3-way novel variant of t(8;21), t(1;21;8)(q21;q22;q22). She presented with gastric discomfort and splenomegaly, and her complete blood count was: white blood cell count 7.96 × 10⁹/l, with 7% blasts; hemoglobin 8.3 g/dl, and platelets 66 × 10⁹/l. Her bone marrow showed increased blasts (32.5%) with a basophilic cytoplasm, salmon-pink granules and Auer rods. Cytogenetic analysis revealed a karyotype of 46,XX,t(1;21;8)(q21;q22;q22), and fluorescence in situ hybridization confirmed a <i>RUNX1-RUNX1T1</i> fusion signal on the derivative chromosome 8. After induction chemotherapy, the patient achieved complete remission and has been stable for 6 months. To the best of our knowledge, this is the first report on the novel variant of t(8;21) involving the breakpoint 1q21 and the third case with a translocation among chromosomes 1, 21 and 8. Although the clinical relevance of variant t(8;21) is still unclear, a review of 24 such cases in the literature does not imply a poorer prognosis of variant t(8;21) than of the classic t(8;21).