SLAMF9 is an orphan receptor of the CD2/SLAM family of leucocyte surface proteins. Examination of SLAMF9 expression and function indicates that SLAMF9 promotes inflammation by specialized subsets of antigen presenting cells. Within healthy liver and circulating mouse PBMCs, SLAMF9 is expressed on CD11b+, Ly6C-, CD11clow , F4/80low , MHC-II+, CX3 CR1+ mononuclear phagocytes as well as plasmacytoid dendritic cells. In addition, SLAMF9 can be found on peritoneal B1 cells and small (F4/80low ), but not large (F4/80high ), peritoneal macrophages. Upon systemic challenge with Salmonella enterica Typhimurium, Slamf9-/- mice were impaired in their ability to clear the infection from the liver. In humans, SLAMF9 is up-regulated upon differentiation of monocytes into macrophages, and LPS stimulation of PMA-differentiated, SLAMF9 knockdown THP-1 cells showed an essential role of SLAMF9 in production of GM-CSF, TNFα, and IL-1β. Taken together, these data implicate SLAMF9 in the initiation of inflammation and clearance of bacterial infection.