The presence of a negatively charged residue in the transmembrane domain of DAP12 precludes its cell surface expression in the absence of a partner receptor containing a positive charge in its transmembrane domain. We utilized this property of DAP12 to screen a BALB / c macrophage cDNA library for novel molecules that induce cell surface expression of DAP12. By this method, we cloned a cell surface receptor with a single Ig (V) domain, a transmembrane lysine residue, and a short cytoplasmic domain. By homology screening of BALB / c macrophage libraries, we identified a second cDNA for a highly homologous receptor. These receptors appear to be the mouse orthologues of a recently identified human cDNA, TREM‐2, so we have designated the receptors as mouse TREM‐2a and TREM‐2b. By Northern blotting, transcripts for TREM‐2 were found in each of three macrophage cell lines but not in a variety of other hematopoietic cell lines. We further demonstrate that TREM‐2a is associated with endogenous DAP12 in macrophage cells, and cross‐linking of TREM‐2a on the surface of macrophages leads to the release of nitric oxide. Our studies define TREM‐2 as a receptor family in mouse macrophages and demonstrate the capacity of these receptors to activate macrophage function through DAP12.