The morphological, ultrastructural, and immunological characteristics of two cases of acute leukemia with t(4;11) (q21;q23) were studied. The blasts from both cases were initially classified as L1 lymphoblasts. Ultrastructural examination indicated a heterogenous blast population in both cases, with some regular lymphoblast-like cells, and others exhibiting nuclear irregularity, small bundles of microfilaments, or large inclusions. In one case at diagnosis, fresh cells expressed B-associated and a myeloid antigen (B4 and 1G10). At the second relapse, the cells from this patient expressed another myeloid-associated antigen, LFA1 molecule, recognized by the monoclonal antibody M232 (CD18). At the end of clinical evolution, a further myeloid antigen was expressed (OKM1), while 8% peroxidase were noted. The other case was studied at diagnosis only and did not express any myeloid marker but expressed the B-associated B4 antigen. Furthermore, the case that exhibited a phenotypic transformation, was noted to show a chromosomal clonal evolution not described so far in other reported cases of t(4;11) acute leukemia. A dual lymphoid-myeloid nature of t(4;11) acute leukemia has been widely discussed. One of the cases reported here supports this hypothesis while the other does not. We would like to underline the possibility of heterogeneity of a case at presentation and transformation to a myeloid phenotype through clonal evolution.