The expression of lymphoid-associated antigens (LAA) on blasts in acute myeloid leukemia (AML) and myeloproliferative disorders in myeloid blast crisis (MPD/MBC) has often been used to establish a diagnosis of acute mixed lineage leukemia (AMLL). The purpose of this study was to determine the incidence of LAA expression in AML and MPD/MBC (Ly+AML); to assess lymphoid differentiation at the genomic level in Ly+AML; and to compare features of Ly+AML with AML and MPD/MBC lacking these antigens (Ly−AML). Seventy-four consecutive cases of AML and MPD/MBC were reviewed for blast morphology, TdT reactivity, and cytochemistry results. Blast immunophenotyping was performed by multiparameter flow cytometry. Acute myeloid leukemia was subtyped according to the FAB classification. Acute myeloid leukemia and MPD/MBC cases expressing one or more of the following antigens, CD2, CD3, CD5, CD7, CD19, or CD20, were considered to be Ly+AML. Immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangement studies were performed by Southern blot analysis using probes for JH, Jkappa, and JBI/BII. Sixteen of the 74 cases (22%) were identified as Ly+AML. Of these, the T-cell-associated markers CD7, CD2, and CD5 were expressed on 7 (44%), 6 (38%), and 4 (25%) Ly+AML cases, respectively. The B-eell associated markers CD19 and CD20 were expressed on two cases (13%) and one (6%) case, respectively. The FAB subtypes were similarly represented among Ly+AML and Ly−AML. Expression of LAA did not correlate with TdT positivity. In nine cases of Ly+AML (7 expressing T-cellassociated antigens and two expressing B-cell-associated antigens), Southern blot analysis revealed no Ig or TCR gene rearrangements. These results suggest that expression of CD2, CD5, and CD7 in otherwise straightforward AML should not be taken as evidence of lymphoid lineage commitment and does not warrant a diagnosis of AMLL.