Intercellular adhesion molecules play an important role in the generation of T lymphocyte–mediated immune responses. Here, we describe a novel accessory molecule, DNAX accessory molecule-1 (DNAM-1), that is constitutively expressed on the majority of peripheral blood T lymphocytes. DNAM-1 is a 65 kDa transmembrane glycoprotein consisting of 318 aa includ- ing two immunoglobulin-like domains. Anti-DNAM-1 monoclonal antibody (MAb) inhibits T and NK cell–mediated cytotoxicity against a variety of tumor cell targets and blocks cytokine production by alloanti- gen-specific T cells. In addition, DNAM-1 is a tyrosine-phosphorylated signal-transducing molecule that participates in primary adhesion during cytotoxic T lymphocyte (CTL)–mediated cytotoxicity.