LAG-3 is a gene localized on the band p13 of human chromosome 12, close to the NK gene complex (NKC), expressed on activated NK cells and encoding a receptor for MHC class II molecules. Recently, LAG-3 has been proposed to define a specific mode of natural killing in mice. The putative role of LAG-3 on human natural killer cytotoxicity has been examined with specific monoclonal antibodies and a recombinant soluble form of LAG-3. Neither the antibodies, which are able to block the interaction with the ligand, nor the recombinant product, which has retained its binding capacity for MHC class II, had an effect on the natural killing of various target cells. Furthermore, in redirected killing assays, none of these antibodies were able to modulate either positively or negatively the cytotoxicity. Taken together, these data show that LAG-3 has no transducing activity involved in NK cytotoxicity, ruling out the existence of a specific mode of natural killing defined by this molecule in humans.