The revised 4th edition of the World Health Organization (WHO) classification of tumours of haematopoietic and lymphoid tissues is based on clinical, morphological, immunophenotypic and genetic features. A case of acute myeloid leukaemia with myelodysplasia-related changes (AML-MRC) in which there was a mixed phenotype of blasts (B-cell/myeloid) has been previously described. We hereby also report an acute leukaemia case that had conflicting morphological and immunophenotypic findings, regarding the revised WHO classification. Patient was a 77 year-old female investigating anaemia for the past few months. Complete blood count (CBC) showed macrocytic anaemia (haemoglobin: 8.3 g/l; MCV: 102 fl) and thrombocytopenia (116 x 109/l), with a normal leukocyte count. Bone marrow assessment was performed when the patient CBC showed circulating blasts. Bone marrow flow cytometry immunophenotyping (FCI) revealed two blast cell populations: one population (about 26% of events) had an immature B-cell phenotype with expression of cytCD22, cytCD79a, CD19, CD22, CD34, CD45(dim), CD58, CD81(dim), CD200, HLA-DR, nuTdT, and an aberrant CD13 and CD123 coexpression; while the other population (about 23% of events) had an immature myeloid phenotype with expression of CD4(dim), CD13, CD25, CD33, CD34, CD58, CD81, CD117, CD123, CD200 and HLA-DR. Neither population expressed cytCD3, cytMPO, CD2, CD3, CD7, CD10, CD11b, CD11c, CD18, CD20, CD36, CD56, CD64 or CD138. If classified isolated, the myeloid population would correspond to an acute myeloid leukaemia (AML) with minimal differentiation and the B-cell population, to a B-lymphoblastic leukaemia/lymphoma (B-ALL). In addition to the FCI data, bone marrow morphological evaluation revealed hypercellularity with severe multilineage dysplasia and two types of blasts with different sizes and morphology, blast cells accounted for 58% of cellularity. Cytogenetic studies showed a karyotype with 45,Xc, t(3;21)(q26;q22). FCI diagnosis considering the EGIL scoring system would be of a biphenotypic acute leukaemia, however to fit into the WHO classification of a mixed-phenotype acute leukaemia (MPAL), the myeloid population would need to express MPO or two monocytic markers, which was not what we observed. Nevertheless, bone marrow morphological findings were suggestive of AML-MRC. There are overlapping features between MPAL and genetically defined AML-MRC. A case series of MPAL identified complex karyotype as the most common genetic abnormality and the WHO classification specifies that AML with complex karyotypes should be classified as AML-MRC. It is recommended that karyotype findings should not be the sole deciding factor to distinguish MPAL from AML-MRC and other factors such as clinical history, morphological findings, immunophenotype and presence of somatic mutations associated with other neoplasms should be considered when leukemic blasts meet criteria for MPAL and the karyotype analysis has myelodysplasia-related abnormalities. Since we did not have access to karyotype results at diagnosis, a descriptive report of FCI and morphological findings was provided. In conclusion, FCI diagnosis of MPAL in the presence of myelodysplasia-related morphological alterations remains a challenge and should take into consideration other laboratory and clinical data.