Exploiting the antitumor effect of natural killer (NK) cells has regained interest in light of data from preclinical and clinical work on the potential of alloreactive NK cells. Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) represent the two most prevalent adult hematological malignancies in the western hemisphere. To evaluate the role of NK cells in the immune surveillance and their therapeutic potential for CLL and MM, tumor cell susceptibility to NK-mediated killing was investigated. Results show relative resistance of tumor cells from CLL as well as MM (73 and 70% of the patients, respectively) to NK-mediated killing. To gain insight into molecular mechanisms of this resistance, the expression of the tolerogenic HLA-G molecule in CLL and MM and its relevance to susceptibility to NK-mediated killing were investigated. HLA-G transcript was found in tumor cells from 89% (n=19) of CLL and 100% (n=9) of MM patients examined. HLA-G1 surface expression was observed in CLL and was very low or undetectable in MM. Notably, blocking of HLA-G1 with specific antibody on CLL samples increased their susceptibility to NK-mediated killing, demonstrating that HLA-G participates in protecting CLL cells from NK-mediated killing and may thus contribute to their immune escape in vivo.