Antiviral immune defenses involve natural killer (NK) cells. We previously showed that the NK activating receptor NKp44 is involved in the functional recognition of H1-type influenza strains by NK. We now investigated the interaction of NKp44 and the hemagglutinin of a primary H5N1 influenza virus isolate. Here we show that recombinant NKp44 recognizes H5-expressing cells and specifically interacts with soluble H5 hemagglutinin. H5 pseudotyped lentiviral particles bind to NK cells expressing NKp44. Following interaction with target cells expressing H5, pseudotyped lentiviral particles, or membrane-associated H5, NK shows NKp44-mediated induced activity. These findings indicate that NKp44-H5 interactions induce functional NK activation.