We recently reported the cloning of two triggering receptors expressed by myeloid cells (TREM), TREM‐2a and TREM‐2b, which are highly homologous to each other. These receptors associate with DAP12, and ligation of TREM‐2 on the surface of macrophages leads to the release of nitric oxide. Using the immunoglobulin (Ig) domain of TREM‐2 to screen a mouse EST database we have isolated a novel receptor, derived from a WEHI‐3 macrophage library, which shows homology to TREM‐2 (20%). The DNA sequence of this receptor has been submitted to Genbank with the name TREM‐3. The predicted amino acid sequence contains a single Ig domain and a transmembrane lysine residue. We found transcripts for TREM‐3 in two macrophage cell lines (RAW264.7 and MT2) but not in P388D1 macrophage cells. TREM‐3 transcripts could also be detected at low levels in T cell lines, but were not detectable in NK, B cell, or mast cell lines. Furthermore, in macrophage cells, transcripts for TREM‐3 were up‐regulated by LPS, but were down‐regulated by IFN‐γ. Like TREM‐1 and TREM‐2, TREM‐3 signals through DAP12, and when TREM‐3 is transfected into an NK cell line it mediates redirected lysis. Thus, TREM‐3 functions as an activating receptor. Analysis of the mouse genome reveals that the gene for TREM‐3 lies adjacent to the gene for TREM‐1 and in close proximity to a number of other single Ig domain receptors, including TREM‐2. Thus, TREM‐3 is a novel member of a family of immunoglobulin receptors that form an innate immune gene complex on chromosome 17.