CD44 is an adhesion molecule that is expressed on hematopoietic cells and has been implicated in the interactions between bone marrow stromal layers and hematopoietic progenitors. The expression of variant forms of CD44, particularly forms containing exon v6, have been associated with poor prognosis in a number of hematological malignancies. The expression of CD44 variants on normal bone marrow (BM), peripheral blood (PBMC) and CD34+ hematopoietic progenitors was compared with those expressed on blasts from 30 patients with acute myeloid leukemia (AML). Normal BM, PBMC and CD34+ progenitor cells were negative for all variants tested by flow cytometry. In contrast exon v3 was expressed on 13%, v4 on 67%, v5 on 19%, v6 on 7% and v7 on 65% of AML cases. RT-PCR and Southern blotting revealed the expression of exons v3, v6, v8, v9 and v10 in normal bone marrow and peripheral blood mononuclear cells and the expression of exons v3, v6, v8 and v10 in CD34+ progenitors. A more complex pattern of variant exon expression was observed in leukemic samples in comparison to normal hematopoietic cells. Sixty-two percent of AML cases expressed exon v3 and 70% exon v6. Exons v4 and v5 were not detected while exons v7, v8, v9 and v10 were detected in 21, 83, 71 and 92% of cases, respectively. In summary, our data demonstrate a striking increase in the complexity of CD44 variant expression in cells from patients with AML, along with surface expression of some variant CD44 proteins. Further analysis will be directed at how these alter the interaction of leukemic blasts with the bone marrow microenvironment and their diagnostic, prognostic and therapeutic potential.