We have identified a common gene structure found in all known members of the CD28 family and have used this conserved structure to include the Natural Cytotoxicity Receptor NKp30 as a CD28 family member. Soluble forms of NKp30 specifically bound to the chronic myelogenous leukemia cell-line K562 and inhibited cytolysis by the human NK line NK-92. This suggested the presence of a functional counter-structure for NKp30 on the surface of K562 and we employed a proteomic approach to identify this molecule. Our analysis identified an unannontated gene specifically from K562 lysates, which when transfected into P815 cells conveyed NKp30-specific binding activity and sensitivity to NKp30-mediated cytolysis by NK cells. The predicted protein and gene structure of this molecule suggested it was a member of the B7 family and we therefore designated it B7h6. Expression analysis suggested limited expression on normal tissues but expression was apparent on a subset of tumor lines and expression correlated well with sensitivity to NKp30-mediated cytolysis further supporting the notion that this molecule serves as a functional counter-structure for NKp30.