Human natural killer (NK) cells are regulated in their cytolytic activity by a delicate interplay between activating and inhibitory signals related to distinct families of triggering and inhibitory receptor proteins. NKp46 is a major NK cell-specific triggering receptor involved in the recognition and lysis of human and murine tumour and virally infected cells. It consists of an extracellular portion, composed of two Ig-like domains, a transmembrane segment and a small cytoplasmic domain. To shed light on the molecular-recognition events involved in NK cytotoxicity triggering mechanisms, the NKp46 extracellular region was cloned, overexpressed, refolded and crystallized. X-ray diffraction data could be collected to a resolution limit of 1.93 A. Crystals of the NKp46 extracellular region belong to the hexagonal space group P6(1) (or P6(5)), with unit-cell parameters a = b = 85.48, c = 59.91 A, gamma = 120 degrees; the asymmetric unit contains one protein chain (197 amino acids).