The destruction of cells capable of initiating and maintaining leukemia challenges the treatment of human acute myeloid leukemia. Recently,CD34⁺/CD38⁻ leukemia progenitors have been defined as new leukemia-initiating cells less mature than colony-forming cells. Here we show that CD34⁺/CD38⁻ leukemia precursors have reduced in vitro sensitivity to daunorubicin, a major drug used in leukemia treatment, in comparison with the CD34⁺/CD38⁺ counterpart, and increased expression of multidrug resistance genes (mrp/lrp). These precursors show lower expression of Fas/Fas-L and Fas-induced apoptosis than CD34⁺/CD38⁺ blasts. Moreover, the CD34⁺/CD38⁻ leukemic subpopulation induces a weaker mixed leukocyte reaction of responding T-lymphocytes than the CD34⁺/CD38⁺ leukemic counterpart, either in a MHC-unmatched or MHC-matched settings. This weaker immunogenicity could be linked to lower expression on CD34⁺/CD38⁻leukemia precursors of major immune response molecules (MHC-DR, LFA-3,B7-1, or B7-2) than CD34⁺/CD38⁺ leukemic cells. Nonetheless, the susceptibility of the immature CD38⁻precursors to cytotoxicity was not different from the sensitivity of the CD38⁺ counterpart. Finally,CD34⁺/CD38⁻ leukemia precursors, in contrast with CD38⁺ precursors, failed, under appropriate conditions, to differentiate into dendritic cells, a central step for antigen recognition. This is to our knowledge the first demonstration that the very immature phenotype of CD34⁺/CD38⁻ leukemic progenitors confers both chemotherapy resistance and decreased capacities to induce an immune response. Because the susceptibility of the immature leukemia cells as cytotoxic targets is maintained, our data underline the importance of improving the initial steps of leukemia recognition, more particularly by defining optimal conditions of dendritic cell transformation of the very immature hematopoietic precursors.