Natural killer (NK) cells direct cytotoxicity against tumor or virally infected cells. NK cell activation depends on a fine balance between inhibitory and activating receptors. NKp44 is a cytotoxicity activating receptor composed of one Ig-like extracellular domain, a transmembrane segment, and a cytoplasmic domain. The 2.2 A crystal structure shows that the NKp44 Ig domain forms a saddle-shaped dimer, where a charged surface groove protrudes from the core structure in each subunit. NKp44 Ig domain disulfide bridge topology defines a new Ig structural subfamily. The data presented are a first step toward understanding the molecular basis for ligand recognition by natural cytotoxicity receptors, whose key role in the immune system is established, but whose cellular ligands are still elusive.