The routine use of panels of monoclonal antibodies has been complementary to the French-American-British (FAB) leukemia classification, and has unmasked the occurrence of mixed acute leukemia (myeloid-lymphoid). It is widely accepted that children with Down's syndrome (DS) have a high incidence of acute leukemia. There is an extensive body of literature emphasizing the cytogenetic findings in these children. However, information as to the immunophenotype is often limited to the lymphoid surface determinants. The authors report two children with DS whose leukemic blasts were studied with a panel of 17 monoclonal antibodies (myeloid, lymphoid, and megakaryocytic) by flow cytometric examination and were classified as biphenotypic acute leukemia. The blast population coexpressed myeloid and T-cell surface markers. The lymphoid origin was ruled out on the basis of negative terminal deoxynucleotidyl transferase and molecular analysis demonstrating germline configuration for the JH and beta TCR genes.