This study tested the hypothesis that the expression of CD112 and CD155 (DNAM‐1 ligands) on leukemic blasts induces a decreased expression of the activating receptor DNAM‐1 on natural killer (NK) cells from acute myeloid leukemia (AML) patients. DNAM‐1 is a co‐receptor involved in the activation of NK cell cytotoxicity after its interaction with its ligands CD112 and CD155 on target cells. Here we study the expression of DNAM‐1 on NK cells and DNAM‐1 ligands on blasts from AML patients stratified by age. The results demonstrate that NK cells from AML patients younger than 65 years have a reduced expression of DNAM‐1 compared with age‐matched controls. The analysis of DNAM‐1 ligands showed a high expression of CD112 and CD155 on leukemic blasts. An inverse correlation between CD112 expression on leukemic blasts and DNAM‐1 expression on NK cells was found. Furthermore, downregulation of DNAM‐1 was induced on healthy donors’ NK cells after in vitro culture with leukemic blasts expressing DNAM‐1 ligands. In conclusion, these results support the hypothesis that receptor–ligand crosslinking downregulates DNAM‐1 expression on NK cells from patients <65 years of age. Considering the relevance of DNAM‐1 in NK recognition and killing of leukemic cells, the reduced expression of this receptor on NK cells from AML patients can represent an additional mechanism of tumor escape.