NK cells are an important component of the innate immune system. Their activity is tightly regulated by activating and inhibitory surface receptors. However, the exact functions of many activating surface receptors, as well as their ligands, still remain to be elucidated. NTB-A is a receptor on the surfaces of human NK, T, and B cells, mediating a signal whose malfunction may be involved in X-linked lymphoproliferative disease. However, the ligand of NTB-A has remained elusive so far. Using trimeric recombinant proteins, we now show that NTB-A is its own ligand. Homophilic interaction of NTB-A enhances NK cell cytotoxicity and influences NK cell proliferation and IFN-gamma secretion. We suggest that NTB-A is an interlymphocyte signaling molecule, which serves to orchestrate the activities of immune cells.