Abstract Spectrins are large, rod-like, multifunctional molecules that participate in maintaining cell structure, signal transmission, and DNA repair. Because little is known about the role of spectrins in normal hematopoiesis and leukemogenesis, we immunohistochemically stained bone marrow biopsy specimens from 81 patients for αI, αII, βI, and βII spectrin isoforms in normal reactive marrow (NRM), myelodysplastic syndrome, myeloproliferative neoplasm, acute myeloid leukemia (AML) with well-characterized cytogenetic abnormalities, acute erythroid leukemia (EryL), and acute megakaryoblastic leukemia (MegL). In NRM, spectrin isoforms were differentially expressed according to cell lineage: αI and βI in erythroid precursors; αII and βII in granulocytes; and βI and βII in megakaryocytes. In contrast, 18 (44%) of 41 AMLs lacked αII spectrin and/or aberrantly expressed βI spectrin (P = .0398; Fisher exact test) and 5 (100%) of 5 EryLs expressed βII spectrin but lacked βI spectrin. The frequent loss and/or gain of spectrin isoforms in AMLs suggests a possible role for spectrin in leukemogenesis.