- Natural killer (NK) cells destroy virus-infected and tumour cells, apparently without the need for previous antigen stimulation1. In part, target cells are recognized by their diminished expression of major histocompatibility complex (MHC) class I molecules, which normally interact with inhibitory receptors on the NK cell surface2,3,4,5,6,7,8. NK cells also express triggering receptors that are specific for non-MHC ligands; but the nature of the ligands recognized on target cells is undefined9,10,11,12,13,14. NKp46 is thought to be the main activating receptor for human NK cells9,15. Here we show that a soluble NKp46–immunoglobulin fusion protein binds to both the haemagglutinin of influenza virus and the haemagglutinin–neuraminidase of parainfluenza virus. In a substantial subset of NK cells, recognition by NKp46 is required to lyse cells expressing the corresponding viral glycoproteins. The binding requires the sialylation of NKp46 oligosaccharides, which is consistent with the known sialic binding capacity of the viral glycoproteins. These findings indicate how NKp46-expressing NK cells may recognize target cells infected by influenza or parainfluenza without the decreased expression of target-cell MHC class I protein.